rs577492

Positions:

• chr1-156130948-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.513+175T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.212 in 152,130 control chromosomes in the GnomAD database, including 7,133 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.21 (7133 hom., cov: 32)
• Consequence: LMNA NM_170707.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.702

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=-0.91).
• BP6: Variant 1-156130948-T-C is Benign according to our data. Variant chr1-156130948-T-C is described in ClinVar as [Benign]. Clinvar id is 672782.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-156130948-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.561 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMNA	NM_170707.4	c.513+175T>C		intron_variant		ENST00000368300.9	NP_733821.1
LMNA	NM_005572.4	c.513+175T>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.513+175T>C		intron_variant		1	NM_170707.4	ENSP00000357283.4
LMNA	ENST00000677389.1	c.513+175T>C		intron_variant			NM_005572.4	ENSP00000503633.1

Frequencies

GnomAD3 genomes AF: 0.211 AC: 32134 AN: 152012 Hom.: 7090 Cov.: 32

Gnomad AFR AF: 0.566

Gnomad AMI AF: 0.0844

Gnomad AMR AF: 0.104

Gnomad ASJ AF: 0.132

Gnomad EAS AF: 0.0227

Gnomad SAS AF: 0.130

Gnomad FIN AF: 0.0565

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.0711

Gnomad OTH AF: 0.170

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

GnomAD4 genome AF: 0.212 AC: 32227 AN: 152130 Hom.: 7133 Cov.: 32 AF XY: 0.208 AC XY: 15486 AN XY: 74402

Gnomad4 AFR AF: 0.567

Gnomad4 AMR AF: 0.104

Gnomad4 ASJ AF: 0.132

Gnomad4 EAS AF: 0.0226

Gnomad4 SAS AF: 0.130

Gnomad4 FIN AF: 0.0565

Gnomad4 NFE AF: 0.0711

Gnomad4 OTH AF: 0.169

Alfa AF: 0.0958 Hom.: 2277

Bravo AF: 0.229

Asia WGS AF: 0.113 AC: 393 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 14, 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	-0.91
CADD	Benign	1.2
DANN	Benign	0.34

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: rs577492; hg19: chr1-156100739;