rs61064130

Positions:

• chr1-156138611-G-A
• chr1-156138611-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PP2 PP5 BP4

The NM_170707.4(LMNA):​c.1822G>A​(p.Gly608Ser) 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. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. G608G) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LMNA NM_170707.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:2
• Conservation: PhyloP100: 2.43

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
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), LMNA. . Gene score misZ 2.3673 (greater than the threshold 3.09). Trascript score misZ 3.0905 (greater than threshold 3.09). GenCC has associacion of gene with familial partial lipodystrophy, Dunnigan type, autosomal recessive Emery-Dreifuss muscular dystrophy, LMNA-related cardiocutaneous progeria syndrome, atrioventricular block, dilated cardiomyopathy 1A, Emery-Dreifuss muscular dystrophy 2, autosomal dominant, atypical Werner syndrome, restrictive dermopathy 1, autosomal semi-dominant severe lipodystrophic laminopathy, Emery-Dreifuss muscular dystrophy 3, autosomal recessive, dilated cardiomyopathy, Charcot-Marie-Tooth disease type 2B1, dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome, arrhythmogenic right ventricular cardiomyopathy, familial isolated dilated cardiomyopathy, mandibuloacral dysplasia with type A lipodystrophy, autosomal dominant Emery-Dreifuss muscular dystrophy, heart-hand syndrome, Slovenian type, congenital muscular dystrophy due to LMNA mutation, lethal restrictive dermopathy, Hutchinson-Gilford progeria syndrome.
• PP5: Variant 1-156138611-G-A is Pathogenic according to our data. Variant chr1-156138611-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 14501.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-156138611-G-A is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.2987898). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMNA	NM_170707.4	c.1822G>A	p.Gly608Ser	missense_variant	11/12	ENST00000368300.9	NP_733821.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMNA	ENST00000368300.9	c.1822G>A	p.Gly608Ser	missense_variant	11/12	1	NM_170707.4	ENSP00000357283	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:2

Revision: no assertion criteria provided

Submissions by phenotype

Hutchinson-Gilford syndrome Pathogenic:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 15, 2003	- -

not provided Other:1

not provided, no classification provided

literature only

Epithelial Biology; Institute of Medical Biology, Singapore

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
CardioboostCm	Benign	0.019
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.38	.;T;.;.;T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.053
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.89	D;D;D;D;D
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.30	T;T;T;T;T
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	1.4	.;L;.;.;.
MutationTaster	Benign	0.18	A;A;A;A;A
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.80	N;N;N;N;N
REVEL	Uncertain	0.34
Sift	Benign	0.53	T;T;T;T;T
Sift4G	Benign	0.49	T;T;T;T;T
Polyphen		0.061	B;B;.;.;.
Vest4		0.41
MutPred		0.17		.;Gain of glycosylation at G608 (P = 0.0011);.;.;.;
MVP		0.81
MPC		0.97
ClinPred		0.56	D
GERP RS		4.9
Varity_R		0.12
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs61064130; hg19: chr1-156108402;