rs4641

chr1-156137743-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_170707.4(LMNA):c.1698C>T(p.His566=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.258 in 1,549,008 control chromosomes in the GnomAD database, including 53,510 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (4005 hom., cov: 33)
  • Exomes 𝑓: 0.26 (49505 hom.)
• Consequence: LMNA NM_170707.4 splice_region, synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:30 O:1
• Conservation: PhyloP100: -1.60

Genes affected

LMNA (HGNC:6636): (lamin A/C) The protein encoded by this gene is part of the nuclear lamina, a two-dimensional matrix of proteins located next to the inner nuclear membrane. The lamin family of proteins make up the matrix and are highly conserved in evolution. During mitosis, the lamina matrix is reversibly disassembled as the lamin proteins are phosphorylated. Lamin proteins are thought to be involved in nuclear stability, chromatin structure and gene expression. Vertebrate lamins consist of two types, A and B. Alternative splicing results in multiple transcript variants. Mutations in this gene lead to several diseases: Emery-Dreifuss muscular dystrophy, familial partial lipodystrophy, limb girdle muscular dystrophy, dilated cardiomyopathy, Charcot-Marie-Tooth disease, and Hutchinson-Gilford progeria syndrome. [provided by RefSeq, May 2022]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 1-156137743-C-T is Benign according to our data. Variant chr1-156137743-C-T is described in ClinVar as [Benign]. Clinvar id is 48048.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156137743-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.6 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.292 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LMNA	NM_170707.4	c.1698C>T	p.His566=	splice_region_variant, synonymous_variant	10/12	ENST00000368300.9
LMNA	NM_005572.4	c.1698C>T	p.His566=	synonymous_variant	10/10	ENST00000677389.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LMNA	ENST00000368300.9	c.1698C>T	p.His566=	splice_region_variant, synonymous_variant	10/12	1	NM_170707.4	P1
LMNA	ENST00000677389.1	c.1698C>T	p.His566=	synonymous_variant	10/10		NM_005572.4

Frequencies

GnomAD3 genomes AF: 0.213 AC: 32355 AN: 152082 Hom.: 4003 Cov.: 33

Gnomad AFR AF: 0.0934

Gnomad AMI AF: 0.346

Gnomad AMR AF: 0.282

Gnomad ASJ AF: 0.284

Gnomad EAS AF: 0.253

Gnomad SAS AF: 0.304

Gnomad FIN AF: 0.170

Gnomad MID AF: 0.255

Gnomad NFE AF: 0.261

Gnomad OTH AF: 0.221

GnomAD3 exomes AF: 0.263 AC: 40459 AN: 153988 Hom.: 5682 AF XY: 0.266 AC XY: 21638 AN XY: 81384

Gnomad AFR exome AF: 0.0906

Gnomad AMR exome AF: 0.324

Gnomad ASJ exome AF: 0.303

Gnomad EAS exome AF: 0.265

Gnomad SAS exome AF: 0.293

Gnomad FIN exome AF: 0.174

Gnomad NFE exome AF: 0.265

Gnomad OTH exome AF: 0.272

GnomAD4 exome AF: 0.263 AC: 367534 AN: 1396808 Hom.: 49505 Cov.: 34 AF XY: 0.264 AC XY: 182035 AN XY: 689016

Gnomad4 AFR exome AF: 0.0862

Gnomad4 AMR exome AF: 0.317

Gnomad4 ASJ exome AF: 0.294

Gnomad4 EAS exome AF: 0.243

Gnomad4 SAS exome AF: 0.294

Gnomad4 FIN exome AF: 0.179

Gnomad4 NFE exome AF: 0.268

Gnomad4 OTH exome AF: 0.261

GnomAD4 genome AF: 0.213 AC: 32371 AN: 152200 Hom.: 4005 Cov.: 33 AF XY: 0.213 AC XY: 15815 AN XY: 74396

Gnomad4 AFR AF: 0.0932

Gnomad4 AMR AF: 0.283

Gnomad4 ASJ AF: 0.284

Gnomad4 EAS AF: 0.252

Gnomad4 SAS AF: 0.305

Gnomad4 FIN AF: 0.170

Gnomad4 NFE AF: 0.261

Gnomad4 OTH AF: 0.223

Alfa AF: 0.257 Hom.: 9011

Bravo AF: 0.216

Asia WGS AF: 0.273 AC: 949 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:30 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:11

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 26, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 22, 2013	His566His in exon 10 of LMNA: This variant is not expected to have clinical sign ificance because it has been identified in 25% (2046/8084) of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/ EVS/; dbSNP rs4641). -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Sep 30, 2019	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 29, 2013	- -

not provided Benign:2 Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 21599722, 21980471, 15205219, 26602028, 26634508) -
not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

Mandibuloacral dysplasia with type A lipodystrophy Benign:2

Benign, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Apr 30, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Charcot-Marie-Tooth disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

-

- -

Emery-Dreifuss muscular dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Mar 09, 2018

- -

Charcot-Marie-Tooth disease type 2B1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Congenital muscular dystrophy due to LMNA mutation Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Dilated cardiomyopathy 1A Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Hutchinson-Gilford syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Charcot-Marie-Tooth disease type 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Limb-Girdle Muscular Dystrophy, Recessive Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Lipoatrophy with Diabetes, Hepatic Steatosis, Hypertrophic Cardiomyopathy, and Leukomelanodermic Papules Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Lethal tight skin contracture syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Familial partial lipodystrophy, Dunnigan type Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Primary dilated cardiomyopathy Benign:1

Benign, no assertion criteria provided

clinical testing

Cohesion Phenomics

Sep 27, 2022

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 07, 2019

General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance;Seen in trans with a mutation or in homozygous state in individual without severe disease for that gene -

Emery-Dreifuss muscular dystrophy 2, autosomal dominant Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
Cadd	Benign	8.6
Dann	Benign	0.88
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs4641; hg19: chr1-156107534; COSMIC: COSV61541921; COSMIC: COSV61541921;