rs955383

Positions:

• chr1-156112239-G-A
• chr1-156112239-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000675667.1(LMNA):​c.-249-2431G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.731 in 151,966 control chromosomes in the GnomAD database, including 40,993 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.73 (40993 hom., cov: 30)
• Consequence: LMNA ENST00000675667.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.539

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.91 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMNA	NM_001282625.2	c.-206-2474G>A		intron_variant			NP_001269554.1
LMNA	NM_001406983.1	c.-206-2474G>A		intron_variant			NP_001393912.1
LMNA	NM_001406984.1	c.-206-2474G>A		intron_variant			NP_001393913.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMNA	ENST00000368301.6	c.-206-2474G>A		intron_variant		2		ENSP00000357284
LMNA	ENST00000675667.1	c.-249-2431G>A		intron_variant				ENSP00000501803
LMNA	ENST00000675939.1	c.-206-2474G>A		intron_variant				ENSP00000502256	P1

Frequencies

GnomAD3 genomes AF: 0.731 AC: 110983 AN: 151848 Hom.: 40956 Cov.: 30

Gnomad AFR AF: 0.638

Gnomad AMI AF: 0.789

Gnomad AMR AF: 0.800

Gnomad ASJ AF: 0.734

Gnomad EAS AF: 0.932

Gnomad SAS AF: 0.880

Gnomad FIN AF: 0.713

Gnomad MID AF: 0.709

Gnomad NFE AF: 0.748

Gnomad OTH AF: 0.734

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

GnomAD4 genome AF: 0.731 AC: 111073 AN: 151966 Hom.: 40993 Cov.: 30 AF XY: 0.733 AC XY: 54407 AN XY: 74254

Gnomad4 AFR AF: 0.638

Gnomad4 AMR AF: 0.800

Gnomad4 ASJ AF: 0.734

Gnomad4 EAS AF: 0.932

Gnomad4 SAS AF: 0.879

Gnomad4 FIN AF: 0.713

Gnomad4 NFE AF: 0.748

Gnomad4 OTH AF: 0.736

Alfa AF: 0.733 Hom.: 4863

Bravo AF: 0.731

Asia WGS AF: 0.893 AC: 3106 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.99
DANN	Benign	0.19

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs955383; hg19: chr1-156082030;