rs915180

Positions:

• chr1-156109292-C-T

Variant summary

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

The ENST00000675667.1(LMNA):​c.-250+2469C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.487 in 152,002 control chromosomes in the GnomAD database, including 19,269 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 0.49 (19269 hom., cov: 32)
• Consequence: LMNA ENST00000675667.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.47

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=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.769 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMNA	NM_001282625.2	c.-206-5421C>T		intron_variant			NP_001269554.1
LMNA	NM_001406983.1	c.-206-5421C>T		intron_variant			NP_001393912.1
LMNA	NM_001406984.1	c.-206-5421C>T		intron_variant			NP_001393913.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMNA	ENST00000368301.6	c.-206-5421C>T		intron_variant		2		ENSP00000357284
LMNA	ENST00000675667.1	c.-250+2469C>T		intron_variant				ENSP00000501803
LMNA	ENST00000675939.1	c.-206-5421C>T		intron_variant				ENSP00000502256	P1

Frequencies

GnomAD3 genomes AF: 0.487 AC: 74004 AN: 151884 Hom.: 19231 Cov.: 32

Gnomad AFR AF: 0.655

Gnomad AMI AF: 0.505

Gnomad AMR AF: 0.403

Gnomad ASJ AF: 0.398

Gnomad EAS AF: 0.789

Gnomad SAS AF: 0.493

Gnomad FIN AF: 0.379

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.403

Gnomad OTH AF: 0.462

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

GnomAD4 genome AF: 0.487 AC: 74091 AN: 152002 Hom.: 19269 Cov.: 32 AF XY: 0.487 AC XY: 36211 AN XY: 74292

Gnomad4 AFR AF: 0.655

Gnomad4 AMR AF: 0.404

Gnomad4 ASJ AF: 0.398

Gnomad4 EAS AF: 0.789

Gnomad4 SAS AF: 0.491

Gnomad4 FIN AF: 0.379

Gnomad4 NFE AF: 0.403

Gnomad4 OTH AF: 0.462

Alfa AF: 0.428 Hom.: 5615

Bravo AF: 0.498

Asia WGS AF: 0.614 AC: 2132 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.79
DANN	Benign	0.71

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs915180; hg19: chr1-156079083;