rs879253992

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1PM2PP2BP4

The NM_170707.4(LMNA):c.161C>T(p.Thr54Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000832 in 1,443,104 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. T54T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000083 ( 0 hom. )

Consequence

LMNA
NM_170707.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 1.38

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 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_170707.4

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=0.37155253).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LMNA	NM_170707.4 linkuse as main transcript	c.161C>T	p.Thr54Met	missense_variant	1/12	ENST00000368300.9
LMNA	NM_005572.4 linkuse as main transcript	c.161C>T	p.Thr54Met	missense_variant	1/10	ENST00000677389.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LMNA	ENST00000368300.9 linkuse as main transcript	c.161C>T	p.Thr54Met	missense_variant	1/12	1	NM_170707.4	P1	P02545-1
LMNA	ENST00000677389.1 linkuse as main transcript	c.161C>T	p.Thr54Met	missense_variant	1/10		NM_005572.4		P02545-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000466

AC:

AN:

214730

Hom.:

AF XY:

0.00

AC XY:

AN XY:

116300

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000623

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000832

AC:

AN:

1443104

Hom.:

Cov.:

AF XY:

0.0000112

AC XY:

AN XY:

716166

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000109

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 15, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 26, 2015	The T54M variant has not been published as pathogenic, nor has it been reported as a benign polymorphism to our knowledge. This variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The T54M variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. In addition, multiple missense variants in nearby residues (L52V, L52P, E53V, E53G, A57P, L59R, R60G, R62G) have been reported in the Human Gene Mutation Database in association with LMNA-related disorders (Stenson et al., 2014), further supporting the functional importance of this region of the protein. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Mar 15, 2023

This missense variant replaces threonine with methionine at codon 54 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 been reported in an individual affected with dilated cardiomyopathy (PMID: 30847666); this individual also carried a different pathogenic missense variant in the LMNA gene. This variant has also been reported in an individual affected with hypertrophic cardiomyopathy and in an individual affected with arrhythmia (PMID: 30847666). This variant has been identified in 1/214730 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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 28, 2017

This sequence change replaces threonine with methionine at codon 54 of the LMNA protein (p.Thr54Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with LMNA-related disease. ClinVar contains an entry for this variant (Variation ID: 245899). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been 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

Nov 30, 2023

Hutchinson-Gilford syndrome;C0410190:Emery-Dreifuss muscular dystrophy 2, autosomal dominant;C0796031:Dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome;C1449563:Dilated cardiomyopathy 1A;C1720860:Familial partial lipodystrophy, Dunnigan type;C1854154:Charcot-Marie-Tooth disease type 2B1;C1857829:Heart-hand syndrome, Slovenian type;C2750035:Emery-Dreifuss muscular dystrophy 3, autosomal recessive;C2750785:Congenital muscular dystrophy due to LMNA mutation;C5399785:Mandibuloacral dysplasia with type A lipodystrophy;C5676942:Restrictive dermopathy 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 04, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

CardioboostCm

Benign

0.015

BayesDel_addAF

Uncertain

0.053

BayesDel_noAF

Benign

-0.16

Cadd

Uncertain

Dann

Uncertain

0.99

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.90

D;D;D;D;D

M_CAP

Uncertain

0.23

MetaRNN

Benign

0.37

T;T;T;T;T

MetaSVM

Uncertain

0.37

MutationAssessor

Benign

1.7

L;.;L;L;L

MutationTaster

Benign

0.71

D;D;D;D;D

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-0.40

N;N;N;N;N

REVEL

Uncertain

0.47

Sift

Benign

0.058

T;T;T;T;T

Sift4G

Benign

0.23

T;T;T;T;T

Polyphen

0.32

B;.;D;P;.

Vest4

0.34

MVP

0.73

MPC

1.5

ClinPred

0.32

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.21

gMVP

0.87

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

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