rs6686943

Positions:

• chr1-156123200-T-C

Variant summary

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

The NM_170707.4(LMNA):​c.357-7417T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 152,188 control chromosomes in the GnomAD database, including 2,107 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 0.11 (2107 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LMNA NM_170707.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.163

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.308 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMNA	NM_170707.4	c.357-7417T>C		intron_variant		ENST00000368300.9	NP_733821.1
LMNA	NM_005572.4	c.357-7417T>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.357-7417T>C		intron_variant		1	NM_170707.4	ENSP00000357283.4
LMNA	ENST00000677389.1	c.357-7417T>C		intron_variant			NM_005572.4	ENSP00000503633.1

Frequencies

GnomAD3 genomes AF: 0.107 AC: 16233 AN: 152070 Hom.: 2105 Cov.: 32

Gnomad AFR AF: 0.312

Gnomad AMI AF: 0.0603

Gnomad AMR AF: 0.0399

Gnomad ASJ AF: 0.0375

Gnomad EAS AF: 0.0221

Gnomad SAS AF: 0.0823

Gnomad FIN AF: 0.0257

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0231

Gnomad OTH AF: 0.0709

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 16 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 12

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

GnomAD4 genome AF: 0.107 AC: 16267 AN: 152188 Hom.: 2107 Cov.: 32 AF XY: 0.105 AC XY: 7778 AN XY: 74422

Gnomad4 AFR AF: 0.312

Gnomad4 AMR AF: 0.0399

Gnomad4 ASJ AF: 0.0375

Gnomad4 EAS AF: 0.0220

Gnomad4 SAS AF: 0.0815

Gnomad4 FIN AF: 0.0257

Gnomad4 NFE AF: 0.0231

Gnomad4 OTH AF: 0.0707

Alfa AF: 0.0555 Hom.: 176

Bravo AF: 0.114

Asia WGS AF: 0.0680 AC: 236 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	8.8
DANN	Benign	0.78

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: rs6686943; hg19: chr1-156092991;