rs372011095

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 7P and 3B. PM1PM2PM5PP2BP4_ModerateBP6

The NM_170707.4(LMNA):c.1376A>G(p.Asn459Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000464 in 1,574,548 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. N459I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000047 ( 0 hom. )

Consequence

LMNA
NM_170707.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:2

Conservation

PhyloP100: 3.78

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM1

In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_170707.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-156136431-A-T is described in Lovd as [Pathogenic].

PP2

Missense variant where missense usually causes diseases, LMNA

BP4

Computational evidence support a benign effect (MetaRNN=0.1749771).

BP6

Variant 1-156136432-A-G is Benign according to our data. Variant chr1-156136432-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178062.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=7, Likely_benign=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LMNA	NM_170707.4 linkuse as main transcript	c.1376A>G	p.Asn459Ser	missense_variant	7/12	ENST00000368300.9
LMNA	NM_005572.4 linkuse as main transcript	c.1376A>G	p.Asn459Ser	missense_variant	7/10	ENST00000677389.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LMNA	ENST00000368300.9 linkuse as main transcript	c.1376A>G	p.Asn459Ser	missense_variant	7/12	1	NM_170707.4	P1	P02545-1
LMNA	ENST00000677389.1 linkuse as main transcript	c.1376A>G	p.Asn459Ser	missense_variant	7/10		NM_005572.4		P02545-2

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000271

AC:

AN:

184812

Hom.:

AF XY:

0.0000101

AC XY:

AN XY:

99130

show subpopulations

Gnomad AFR exome

AF:

0.0000914

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000519

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000471

AC:

AN:

1422352

Hom.:

Cov.:

AF XY:

0.0000483

AC XY:

AN XY:

704352

show subpopulations

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:

0.0000121

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000586

Gnomad4 OTH exome

AF:

0.0000340

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.0000482

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:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000113

Hom.:

Bravo

AF:

0.0000302

ESP6500AA

AF:

0.000228

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000169

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 02, 2017	The p.Asn459Ser variant (rs372011095) has been previously observed in a cohort of cardiomyopathy, dysrhythmias, or cardiac progeria patients (Rodriguez 2008), although no other specific clinical information is provided in relation to this patient population. This variant is also listed in the Genome Aggregation Database (gnomAD) browser with an overall frequency of 0.003% (identified in 6 out of 210,462 chromosomes). The asparagine at codon 459 is moderately conserved considering 11 species (Alamut software v2.9), and computational analyses return mixed results regarding the effect of this variant on LMNA protein structure/function (SIFT: tolerated, PolyPhen2: benign, and Mutation Taster: disease causing). However, variants in nearby amino acids have been associated with Emery-Dreifuss muscular dystrophy (selected reference: Helbling-Leclerc 2002). This variant is also listed in the ClinVar database with conflicting interpretations of pathogenicity (Variation ID: 178062). Thus, based on the available information, the clinical significance of the p.Asn459Ser variant cannot be determined with certainty. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 13, 2018	A variant of uncertain significance has been identified in the LMNA gene. The N459S variant has been reported by Rodriguez et al. (2008) in a cohort of patients with cardiomyopathy, dysrhythmias, or cardiac progeria; however, phenotypic characteristics of the patient with the N459S variant was not defined. The N459S variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The N459S variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Nevertheless, the N459S variant is located in the globular carboxy-terminal tail region of the LMNA gene. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 13, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 24, 2019	- -

Cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Nov 06, 2023

This missense variant replaces asparagine with serine at codon 459 of the lamin A/C proteins. 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 cardiovascular disorders in the literature. This variant has been identified in 7/216196 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. -

Primary dilated cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Feb 05, 2024

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 23, 2023

The p.N459S variant (also known as c.1376A>G), located in coding exon 7 of the LMNA gene, results from an A to G substitution at nucleotide position 1376. The asparagine at codon 459 is replaced by serine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 17, 2014

Asn459Ser in exon 7 of LMNA: This variant is not expected to have clinical signi ficance due to a lack of conservation across species, including mammals. Of note , multiple mammals (cat, dog, walrus, seal, fox, and two bat species) have a ser ine (Ser) at this position despite high nearby amino acid conservation. It has a lso been identified in 1/4378 African American chromosomes by the NHLBI Exome S equencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs372011095). Additi onal computational analyses (AlignGVGD, PolyPhen2, SIFT) do not suggest a high l ikelihood of impact to the protein. Asn459Ser in exon 7 of LMNA (rs372011095; a llele frequency = 1/4378) ** -

Charcot-Marie-Tooth disease type 2

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 03, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

CardioboostCm

Benign

0.0037

BayesDel_addAF

Benign

-0.039

BayesDel_noAF

Benign

-0.090

Cadd

Benign

Dann

Uncertain

0.99

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.17

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.78

T;T;T;T;T;T;T;T

M_CAP

Benign

0.050

MetaRNN

Benign

0.17

T;T;T;T;T;T;T;T

MetaSVM

Uncertain

0.0081

MutationAssessor

Benign

0.33

N;N;N;N;.;.;.;.

MutationTaster

Benign

0.95

D;D;D;D;D;D;D;D;D

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.99

N;N;N;N;N;N;N;N

REVEL

Uncertain

0.39

Sift

Uncertain

0.026

D;T;D;D;T;D;D;T

Sift4G

Uncertain

0.023

D;T;D;D;T;T;T;D

Polyphen

0.012

B;B;B;.;.;B;.;.

Vest4

0.19

MVP

0.69

MPC

0.27

ClinPred

0.066

GERP RS

3.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.25

gMVP

0.36

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over