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rs142000963

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PM5PP2

The NM_170707.4(LMNA):c.1930C>A(p.Arg644Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as not provided (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R644C) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

LMNA
NM_170707.4 missense

Scores

2
10
6

Clinical Significance

not provided no classification provided O:1

Conservation

PhyloP100: 3.06
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr1-156138719-C-T is described in Lovd as [Pathogenic].
PP2
Missense variant where missense usually causes diseases, LMNA

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
LMNANM_170707.4 linkuse as main transcriptc.1930C>A p.Arg644Ser missense_variant 11/12 ENST00000368300.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
LMNAENST00000368300.9 linkuse as main transcriptc.1930C>A p.Arg644Ser missense_variant 11/121 NM_170707.4 P1P02545-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: not provided
Submissions summary: Other:1
Revision: no classification provided
LINK: link

Submissions by phenotype

not provided Other:1
not provided, no classification providedliterature onlyEpithelial Biology; Institute of Medical Biology, Singapore-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.64
CardioboostCm
Benign
0.00087
BayesDel_addAF
Pathogenic
0.24
D
BayesDel_noAF
Uncertain
0.11
Cadd
Pathogenic
26
Dann
Uncertain
1.0
Eigen
Benign
0.079
Eigen_PC
Benign
0.21
FATHMM_MKL
Uncertain
0.79
D
LIST_S2
Uncertain
0.89
D;D;D;D;D
M_CAP
Uncertain
0.18
D
MetaRNN
Uncertain
0.44
T;T;T;T;T
MetaSVM
Uncertain
0.11
D
MutationTaster
Benign
0.98
D;D;D;D;D
PrimateAI
Uncertain
0.52
T
PROVEAN
Benign
-0.50
N;N;N;N;N
REVEL
Uncertain
0.46
Sift
Uncertain
0.0070
D;D;D;D;D
Sift4G
Benign
0.13
T;T;T;T;T
Polyphen
0.63
P;P;.;.;.
Vest4
0.69
MutPred
0.39
.;Loss of sheet (P = 0.0315);.;.;.;
MVP
0.92
MPC
0.50
ClinPred
0.77
D
GERP RS
4.7
Varity_R
0.20
gMVP
0.69

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
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.

Other links and lift over

dbSNP: rs142000963; hg19: chr1-156108510; API