rs4661146

chr1-156090359-G-C

Variant summary

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

The NM_001406983.1(LMNA):c.-207+7175G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.229 in 152,066 control chromosomes in the GnomAD database, including 5,038 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 0.23 (5037 hom., cov: 32)
  • Exomes 𝑓: 0.25 (1 hom.)
• Consequence: LMNA NM_001406983.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.808

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=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.69 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LMNA	NM_001282625.2	c.-318-112G>C		intron_variant
LMNA	NM_001406983.1	c.-207+7175G>C		intron_variant
LMNA	NM_001406984.1	c.-207+7175G>C		intron_variant
LMNA	NM_001407002.1	c.-651+7175G>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LMNA	ENST00000368301.6	c.-318-112G>C		intron_variant		2
LMNA	ENST00000470835.1	n.271-640G>C		intron_variant, non_coding_transcript_variant		3
LMNA	ENST00000502751.5	n.328+7175G>C		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.228 AC: 34708 AN: 151924 Hom.: 5022 Cov.: 32

Gnomad AFR AF: 0.318

Gnomad AMI AF: 0.170

Gnomad AMR AF: 0.217

Gnomad ASJ AF: 0.206

Gnomad EAS AF: 0.709

Gnomad SAS AF: 0.299

Gnomad FIN AF: 0.112

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.156

Gnomad OTH AF: 0.211

GnomAD4 exome AF: 0.250 AC: 6 AN: 24 Hom.: 1 AF XY: 0.250 AC XY: 4 AN XY: 16

Gnomad4 AFR exome AF: 0.00

Gnomad4 FIN exome AF: 0.300

Gnomad4 NFE exome AF: 0.250

GnomAD4 genome AF: 0.229 AC: 34758 AN: 152042 Hom.: 5037 Cov.: 32 AF XY: 0.230 AC XY: 17088 AN XY: 74334

Gnomad4 AFR AF: 0.318

Gnomad4 AMR AF: 0.217

Gnomad4 ASJ AF: 0.206

Gnomad4 EAS AF: 0.709

Gnomad4 SAS AF: 0.300

Gnomad4 FIN AF: 0.112

Gnomad4 NFE AF: 0.156

Gnomad4 OTH AF: 0.214

Alfa AF: 0.184 Hom.: 389

Bravo AF: 0.244

Asia WGS AF: 0.466 AC: 1614 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	1.6
Dann	Benign	0.72

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs4661146; hg19: chr1-156060150;