rs80356813

Positions:

• chr1-156138550-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_170707.4(LMNA):​c.1761G>A​(p.Leu587Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00189 in 1,612,680 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L587L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0020 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (4 hom.)
• Consequence: LMNA NM_170707.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:21
• Conservation: PhyloP100: 1.18

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]

LMNA (HGNC:):

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 1-156138550-G-A is Benign according to our data. Variant chr1-156138550-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 36477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156138550-G-A is described in Lovd as [Benign]. Variant chr1-156138550-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.18 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 2 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMNA	NM_170707.4	c.1761G>A	p.Leu587Leu	synonymous_variant	11/12	ENST00000368300.9	NP_733821.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMNA	ENST00000368300.9	c.1761G>A	p.Leu587Leu	synonymous_variant	11/12	1	NM_170707.4	ENSP00000357283.4

Frequencies

GnomAD3 genomes AF: 0.00196 AC: 298 AN: 152260 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00546

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00322

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00190 AC: 463 AN: 244258 Hom.: 0 AF XY: 0.00188 AC XY: 251 AN XY: 133310

Gnomad AFR exome AF: 0.000131

Gnomad AMR exome AF: 0.0000582

Gnomad ASJ exome AF: 0.000707

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00692

Gnomad NFE exome AF: 0.00273

Gnomad OTH exome AF: 0.00150

GnomAD4 exome AF: 0.00188 AC: 2744 AN: 1460302 Hom.: 4 Cov.: 32 AF XY: 0.00187 AC XY: 1360 AN XY: 726476

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.0000672

Gnomad4 ASJ exome AF: 0.000920

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00635

Gnomad4 NFE exome AF: 0.00206

Gnomad4 OTH exome AF: 0.00148

GnomAD4 genome AF: 0.00196 AC: 298 AN: 152378 Hom.: 2 Cov.: 32 AF XY: 0.00205 AC XY: 153 AN XY: 74518

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00546

Gnomad4 NFE AF: 0.00322

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00272 Hom.: 1

Bravo AF: 0.00119

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00185

EpiControl AF: 0.00202

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:21

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:9

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 19, 2015	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
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	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 29, 2015	p.Leu587Leu in exon 11 of LMNA: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 0.7% (36/5272) of Finnish chromosomes and 0.3% (187/59480) of European chromosomes by the Exome Ag gregation Consortium (ExAC, http://exac.broadinstitute.org/; dbSNP rs80356813). -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 19, 2017	- -
Likely 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	GeneDx	Mar 03, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	LMNA: BP4, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Cardiomyopathy Benign:3

Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Feb 24, 2016	- -
Benign, no assertion criteria provided	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 20, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 08, 2018	- -

Charcot-Marie-Tooth disease Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

-

- -

Charcot-Marie-Tooth disease type 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Primary dilated cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Feb 05, 2024

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 02, 2015

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	11
DANN	Benign	0.92

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: rs80356813; hg19: chr1-156108341;