1-156137072-C-T

Variant names:

• chr1-156137072-C-T
• rs553016
• ENST00000368298.2:n.1280C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000368298.2(LMNA):​n.1280C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0883 in 1,613,822 control chromosomes in the GnomAD database, including 11,376 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (3906 hom., cov: 32)
  • Exomes 𝑓: 0.080 (7470 hom.)
• Consequence: LMNA ENST00000368298.2 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: 0.386
• Publications: 16 publications found

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 Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• dilated cardiomyopathy 1A

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Orphanet
• familial partial lipodystrophy, Dunnigan type

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
• Hutchinson-Gilford progeria syndrome

  Inheritance: AD, SD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• restrictive dermopathy 2

  Inheritance: AR, AD Classification: DEFINITIVE, LIMITED Submitted by: G2P
• Emery-Dreifuss muscular dystrophy 2, autosomal dominant

  Inheritance: SD, AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• atrioventricular block

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• heart-hand syndrome, Slovenian type

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, G2P
• Charcot-Marie-Tooth disease type 2B1

  Inheritance: AR, AD Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: G2P, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• Emery-Dreifuss muscular dystrophy 3, autosomal recessive

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• mandibuloacral dysplasia with type A lipodystrophy

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• atrial fibrillation

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• atypical Werner syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal dominant Emery-Dreifuss muscular dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• congenital muscular dystrophy due to LMNA mutation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• lethal restrictive dermopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• LMNA-related cardiocutaneous progeria syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive Emery-Dreifuss muscular dystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal semi-dominant severe lipodystrophic laminopathy

  Inheritance: SD Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 1-156137072-C-T is Benign according to our data. Variant chr1-156137072-C-T is described in ClinVar as Benign. ClinVar VariationId is 66834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.407 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000368298.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LMNA	NM_170707.4	MANE Select	c.1489-41C>T		intron	N/A	NP_733821.1
	LMNA	NM_005572.4	MANE Plus Clinical	c.1489-41C>T		intron	N/A	NP_005563.1
	LMNA	NM_001406985.1		c.1489-41C>T		intron	N/A	NP_001393914.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LMNA	ENST00000368298.2	TSL:1	n.1280C>T		non_coding_transcript_exon	Exon 3 of 3
	LMNA	ENST00000368300.9	TSL:1 MANE Select	c.1489-41C>T		intron	N/A	ENSP00000357283.4
	LMNA	ENST00000677389.1	MANE Plus Clinical	c.1489-41C>T		intron	N/A	ENSP00000503633.1

Frequencies

GnomAD3 genomes AF: 0.167 AC: 25410 AN: 151958 Hom.: 3896 Cov.: 32

Gnomad AFR AF: 0.413

Gnomad AMI AF: 0.0844

Gnomad AMR AF: 0.0904

Gnomad ASJ AF: 0.132

Gnomad EAS AF: 0.0228

Gnomad SAS AF: 0.127

Gnomad FIN AF: 0.0567

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.0703

Gnomad OTH AF: 0.136

GnomAD2 exomes AF: 0.0992 AC: 24904 AN: 251016 AF XY: 0.0979

Gnomad AFR exome AF: 0.428

Gnomad AMR exome AF: 0.0634

Gnomad ASJ exome AF: 0.132

Gnomad EAS exome AF: 0.0192

Gnomad FIN exome AF: 0.0556

Gnomad NFE exome AF: 0.0716

Gnomad OTH exome AF: 0.0906

GnomAD4 exome AF: 0.0801 AC: 117113 AN: 1461746 Hom.: 7470 Cov.: 32 AF XY: 0.0822 AC XY: 59756 AN XY: 727168

African (AFR) AF: 0.430 AC: 14398 AN: 33478

American (AMR) AF: 0.0661 AC: 2955 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.130 AC: 3410 AN: 26136

East Asian (EAS) AF: 0.0159 AC: 633 AN: 39688

South Asian (SAS) AF: 0.140 AC: 12095 AN: 86252

European-Finnish (FIN) AF: 0.0543 AC: 2901 AN: 53386

Middle Eastern (MID) AF: 0.153 AC: 882 AN: 5768

European-Non Finnish (NFE) AF: 0.0664 AC: 73860 AN: 1111936

Other (OTH) AF: 0.0990 AC: 5979 AN: 60382

GnomAD4 genome AF: 0.167 AC: 25450 AN: 152076 Hom.: 3906 Cov.: 32 AF XY: 0.164 AC XY: 12218 AN XY: 74348

African (AFR) AF: 0.413 AC: 17085 AN: 41416

American (AMR) AF: 0.0903 AC: 1378 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.132 AC: 458 AN: 3472

East Asian (EAS) AF: 0.0226 AC: 117 AN: 5172

South Asian (SAS) AF: 0.127 AC: 614 AN: 4830

European-Finnish (FIN) AF: 0.0567 AC: 602 AN: 10616

Middle Eastern (MID) AF: 0.197 AC: 58 AN: 294

European-Non Finnish (NFE) AF: 0.0703 AC: 4776 AN: 67984

Other (OTH) AF: 0.135 AC: 285 AN: 2112

Alfa AF: 0.102 Hom.: 5671

Bravo AF: 0.179

ClinVar

Significance: Benign

Submissions summary: Benign:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2 Other:1

Epithelial Biology; Institute of Medical Biology, Singapore

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	7.1
DANN	Benign	0.33
PhyloP100		0.39
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs553016; hg19: chr1-156106863; COSMIC: COSV61542554; COSMIC: COSV61542554;