rs508641

Positions:

• chr1-156130348-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_170707.4(LMNA):​c.357-269T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0812 in 151,902 control chromosomes in the GnomAD database, including 795 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.081 (795 hom., cov: 32)
• Consequence: LMNA NM_170707.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0390

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 1-156130348-T-C is Benign according to our data. Variant chr1-156130348-T-C is described in ClinVar as [Benign]. Clinvar id is 668923.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-156130348-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.168 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMNA	NM_170707.4	c.357-269T>C		intron_variant		ENST00000368300.9	NP_733821.1
LMNA	NM_005572.4	c.357-269T>C		intron_variant		ENST00000677389.1	NP_005563.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMNA	ENST00000368300.9	c.357-269T>C		intron_variant		1	NM_170707.4	ENSP00000357283.4
LMNA	ENST00000677389.1	c.357-269T>C		intron_variant			NM_005572.4	ENSP00000503633.1

Frequencies

GnomAD3 genomes AF: 0.0811 AC: 12314 AN: 151782 Hom.: 791 Cov.: 32

Gnomad AFR AF: 0.171

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.0564

Gnomad ASJ AF: 0.0949

Gnomad EAS AF: 0.000773

Gnomad SAS AF: 0.0514

Gnomad FIN AF: 0.0307

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.0479

Gnomad OTH AF: 0.0795

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0812 AC: 12331 AN: 151902 Hom.: 795 Cov.: 32 AF XY: 0.0800 AC XY: 5939 AN XY: 74240

Gnomad4 AFR AF: 0.171

Gnomad4 AMR AF: 0.0563

Gnomad4 ASJ AF: 0.0949

Gnomad4 EAS AF: 0.000775

Gnomad4 SAS AF: 0.0516

Gnomad4 FIN AF: 0.0307

Gnomad4 NFE AF: 0.0479

Gnomad4 OTH AF: 0.0787

Alfa AF: 0.0668 Hom.: 66

Bravo AF: 0.0869

Asia WGS AF: 0.0360 AC: 125 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 18, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	13
DANN	Benign	0.69

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: rs508641; hg19: chr1-156100139;