rs752598065

chr1-156138708-A-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Strong

The NM_170707.4(LMNA):c.1919A>G(p.Asn640Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,198 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N640D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: LMNA NM_170707.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: -0.263

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, LMNA
• BP4: Computational evidence support a benign effect (MetaRNN=0.030963838).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LMNA	NM_170707.4	c.1919A>G	p.Asn640Ser	missense_variant	11/12	ENST00000368300.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LMNA	ENST00000368300.9	c.1919A>G	p.Asn640Ser	missense_variant	11/12	1	NM_170707.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151902 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000803 AC: 2 AN: 249084 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135164

Gnomad AFR exome AF: 0.0000627

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461296 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 726982

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151902 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74206

Gnomad4 AFR AF: 0.0000484

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 07, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 18, 2020	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Familial partial lipodystrophy, Dunnigan type Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Oct 03, 2022

The c.1919A>G, p.(Asn640Ser) missense variant identified in the LMNA gene has not been reported in affected individuals in the literature. The variant has been reported in the ClinVar database as a Variant of Uncertain Significance (Variation ID: 288276). The c.1919A>G variant is observed in 5 alleles (~0.0008% allele frequency with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8), suggesting it is not a common benign variant in the populations represented in those databases. The c.1919A>G variant is located in exon 11 of this 12-exon gene, and predicted to replace a weakly conserved asparagine amino acid with serine at position 640. In silico predictions are inconclusive of deleterious effect (REVEL score = 0.333); however, there are no functional studies to support or refute these predictions. Based on available evidence the c.1919A>G, p.(Asn640Ser) missense variant identified in the LMNA gene is classified as a Variant of Uncertain Significance. -

Primary dilated cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Oct 27, 2023

This missense variant replaces asparagine with serine at codon 640 of the LMNA protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with LMNA-related disorders in the literature. This variant has been identified in 2/249084 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Charcot-Marie-Tooth disease type 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Nov 22, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
CardioboostCm	Benign	0.0080
BayesDel_addAF	Benign	-0.075	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	5.6
Dann	Benign	0.86
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.055	N
LIST_S2	Benign	0.76	T;T;T;T;T
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.031	T;T;T;T;T
MetaSVM	Benign	-0.86	T
MutationTaster	Benign	1.0	D;N;N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.060	N;N;N;N;N
REVEL	Uncertain	0.33
Sift	Benign	0.66	T;T;T;T;T
Sift4G	Benign	0.39	T;T;T;T;T
Polyphen		0.0	B;B;.;.;.
Vest4		0.20
MutPred		0.13		.;Gain of phosphorylation at N640 (P = 0.0739);.;.;.;
MVP		0.76
MPC		0.27
ClinPred		0.026	T
GERP RS		2.5
Varity_R		0.026
gMVP		0.46

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: rs752598065; hg19: chr1-156108499;