chr1-156137756-C-G

Position:

• chr1-156137756-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PM5 BP4

The NM_005572.4(LMNA):​c.1711C>G​(p.Arg571Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R571H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LMNA NM_005572.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.30

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-156137756-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 14485.We mark this variant Likely_pathogenic, oryginal submissions are: {not_provided=2, Likely_pathogenic=1, Pathogenic=1, Uncertain_significance=4}.
• BP4: Computational evidence support a benign effect (MetaRNN=0.26681936).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LMNA	NM_005572.4	c.1711C>G	p.Arg571Gly	missense_variant	10/10	ENST00000677389.1
LMNA	NM_170707.4	c.1698+13C>G		intron_variant		ENST00000368300.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LMNA	ENST00000677389.1	c.1711C>G	p.Arg571Gly	missense_variant	10/10		NM_005572.4
LMNA	ENST00000368300.9	c.1698+13C>G		intron_variant		1	NM_170707.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Benign	20
DANN	Uncertain	0.99
Eigen	Benign	-0.10
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.57	T;T;T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.27	T;T;T
MetaSVM	Benign	-0.64	T
MutationTaster	Benign	1.0	D;D;D;D;D;N;N;N;N
PROVEAN	Benign	-0.35	N;.;N
REVEL	Uncertain	0.42
Sift	Pathogenic	0.0	D;.;D
Sift4G	Benign	0.24	T;D;T
Polyphen		0.0010	B;.;B
Vest4		0.39
MutPred		0.29		.;.;Loss of solvent accessibility (P = 0.0044);
MVP		0.89
ClinPred		0.82	D
GERP RS		5.6

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: rs80338938; hg19: chr1-156107547;