rs520973

Variant names:

• chr1-156138228-C-T
• rs520973
• NM_170707.4:c.1699-260C>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_170707.4(LMNA):​c.1699-260C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.109 in 586,598 control chromosomes in the GnomAD database, including 6,825 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (4141 hom., cov: 32)
  • Exomes 𝑓: 0.088 (2684 hom.)
• Consequence: LMNA NM_170707.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 1-156138228-C-T is Benign according to our data. Variant chr1-156138228-C-T is described in ClinVar as [Benign]. Clinvar id is 683615.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156138228-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.42 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LMNA	NM_170707.4	c.1699-260C>T		intron_variant	Intron 10 of 11	ENST00000368300.9	NP_733821.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LMNA	ENST00000368300.9	c.1699-260C>T		intron_variant	Intron 10 of 11	1	NM_170707.4	ENSP00000357283.4

Frequencies

GnomAD3 genomes AF: 0.171 AC: 25965 AN: 152086 Hom.: 4130 Cov.: 32

Gnomad AFR AF: 0.425

Gnomad AMI AF: 0.0844

Gnomad AMR AF: 0.0910

Gnomad ASJ AF: 0.131

Gnomad EAS AF: 0.0225

Gnomad SAS AF: 0.127

Gnomad FIN AF: 0.0564

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.0704

Gnomad OTH AF: 0.137

GnomAD4 exome AF: 0.0877 AC: 38116 AN: 434394 Hom.: 2684 Cov.: 4 AF XY: 0.0903 AC XY: 20566 AN XY: 227840

Gnomad4 AFR exome AF: 0.429

Gnomad4 AMR exome AF: 0.0779

Gnomad4 ASJ exome AF: 0.129

Gnomad4 EAS exome AF: 0.0154

Gnomad4 SAS exome AF: 0.140

Gnomad4 FIN exome AF: 0.0538

Gnomad4 NFE exome AF: 0.0715

Gnomad4 OTH exome AF: 0.105

GnomAD4 genome AF: 0.171 AC: 26006 AN: 152204 Hom.: 4141 Cov.: 32 AF XY: 0.168 AC XY: 12478 AN XY: 74422

Gnomad4 AFR AF: 0.425

Gnomad4 AMR AF: 0.0908

Gnomad4 ASJ AF: 0.131

Gnomad4 EAS AF: 0.0224

Gnomad4 SAS AF: 0.127

Gnomad4 FIN AF: 0.0564

Gnomad4 NFE AF: 0.0703

Gnomad4 OTH AF: 0.136

Alfa AF: 0.155 Hom.: 623

Bravo AF: 0.183

Asia WGS AF: 0.0970 AC: 336 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 18, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.84
CADD	Benign	0.12
DANN	Benign	0.31
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs520973; hg19: chr1-156108019;