rs593987

Positions:

• chr1-156126596-G-A

Variant summary

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

The NM_001406988.1(LMNA):​c.-79G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0624 in 894,986 control chromosomes in the GnomAD database, including 3,271 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (1496 hom., cov: 32)
  • Exomes 𝑓: 0.054 (1775 hom.)
• Consequence: LMNA NM_001406988.1 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.35

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004555613).
• BP6: Variant 1-156126596-G-A is Benign according to our data. Variant chr1-156126596-G-A is described in ClinVar as [Benign]. Clinvar id is 672778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.245 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMNA	NM_170707.4	c.357-4021G>A		intron_variant		ENST00000368300.9	NP_733821.1
LMNA	NM_005572.4	c.357-4021G>A		intron_variant		ENST00000677389.1	NP_005563.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMNA	ENST00000368300.9	c.357-4021G>A		intron_variant		1	NM_170707.4	ENSP00000357283.4
LMNA	ENST00000677389.1	c.357-4021G>A		intron_variant			NM_005572.4	ENSP00000503633.1

Frequencies

GnomAD3 genomes AF: 0.103 AC: 15734 AN: 152154 Hom.: 1480 Cov.: 32

Gnomad AFR AF: 0.249

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.0632

Gnomad ASJ AF: 0.0948

Gnomad EAS AF: 0.000960

Gnomad SAS AF: 0.0540

Gnomad FIN AF: 0.0310

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.0481

Gnomad OTH AF: 0.0963

GnomAD3 exomes AF: 0.0565 AC: 11867 AN: 209946 Hom.: 625 AF XY: 0.0562 AC XY: 6469 AN XY: 115132

Gnomad AFR exome AF: 0.254

Gnomad AMR exome AF: 0.0448

Gnomad ASJ exome AF: 0.0891

Gnomad EAS exome AF: 0.000817

Gnomad SAS exome AF: 0.0572

Gnomad FIN exome AF: 0.0301

Gnomad NFE exome AF: 0.0478

Gnomad OTH exome AF: 0.0624

GnomAD4 exome AF: 0.0540 AC: 40077 AN: 742714 Hom.: 1775 Cov.: 10 AF XY: 0.0543 AC XY: 21422 AN XY: 394176

Gnomad4 AFR exome AF: 0.257

Gnomad4 AMR exome AF: 0.0461

Gnomad4 ASJ exome AF: 0.0898

Gnomad4 EAS exome AF: 0.000345

Gnomad4 SAS exome AF: 0.0607

Gnomad4 FIN exome AF: 0.0291

Gnomad4 NFE exome AF: 0.0485

Gnomad4 OTH exome AF: 0.0665

GnomAD4 genome AF: 0.104 AC: 15785 AN: 152272 Hom.: 1496 Cov.: 32 AF XY: 0.102 AC XY: 7614 AN XY: 74486

Gnomad4 AFR AF: 0.249

Gnomad4 AMR AF: 0.0630

Gnomad4 ASJ AF: 0.0948

Gnomad4 EAS AF: 0.000963

Gnomad4 SAS AF: 0.0541

Gnomad4 FIN AF: 0.0310

Gnomad4 NFE AF: 0.0481

Gnomad4 OTH AF: 0.0957

Alfa AF: 0.0796 Hom.: 364

Bravo AF: 0.113

TwinsUK AF: 0.0396 AC: 147

ALSPAC AF: 0.0423 AC: 163

ESP6500AA AF: 0.229 AC: 401

ESP6500EA AF: 0.0490 AC: 195

ExAC AF: 0.0541 AC: 6250

Asia WGS AF: 0.0460 AC: 159 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	0.24
DANN	Benign	0.53
DEOGEN2	Benign	0.22	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0012	N
LIST_S2	Benign	0.27	T
MetaRNN	Benign	0.0046	T
MetaSVM	Benign	-0.90	T
PROVEAN	Benign	1.7	N
REVEL	Benign	0.088
Sift	Uncertain	0.011	D
MutPred		0.17		Gain of solvent accessibility (P = 0.0306);
ClinPred		0.012	T
GERP RS		-6.7

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: rs593987; hg19: chr1-156096387; COSMIC: COSV61542733;