rs1131521

Positions:

• chr18-23933804-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_198129.4(LAMA3):​c.8731C>T​(p.Leu2911=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.197 in 1,613,476 control chromosomes in the GnomAD database, including 32,634 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2284 hom., cov: 33)
  • Exomes 𝑓: 0.20 (30350 hom.)
• Consequence: LAMA3 NM_198129.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.542

Genes affected

LAMA3 (HGNC:6483): (laminin subunit alpha 3) The protein encoded by this gene belongs to the laminin family of secreted molecules. Laminins are heterotrimeric molecules that consist of alpha, beta, and gamma subunits that assemble through a coiled-coil domain. Laminins are essential for formation and function of the basement membrane and have additional functions in regulating cell migration and mechanical signal transduction. This gene encodes an alpha subunit and is responsive to several epithelial-mesenchymal regulators including keratinocyte growth factor, epidermal growth factor and insulin-like growth factor. Mutations in this gene have been identified as the cause of Herlitz type junctional epidermolysis bullosa and laryngoonychocutaneous syndrome. Alternative splicing and alternative promoter usage result in multiple transcript variants. [provided by RefSeq, Dec 2014]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 18-23933804-C-T is Benign according to our data. Variant chr18-23933804-C-T is described in ClinVar as [Benign]. Clinvar id is 255578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.542 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.225 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMA3	NM_198129.4	c.8731C>T	p.Leu2911=	synonymous_variant	67/75	ENST00000313654.14
LAMA3	NM_000227.6	c.3904C>T	p.Leu1302=	synonymous_variant	30/38	ENST00000269217.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMA3	ENST00000313654.14	c.8731C>T	p.Leu2911=	synonymous_variant	67/75	1	NM_198129.4	P1
LAMA3	ENST00000269217.11	c.3904C>T	p.Leu1302=	synonymous_variant	30/38	1	NM_000227.6

Frequencies

GnomAD3 genomes AF: 0.156 AC: 23694 AN: 152142 Hom.: 2277 Cov.: 33

Gnomad AFR AF: 0.0425

Gnomad AMI AF: 0.0811

Gnomad AMR AF: 0.148

Gnomad ASJ AF: 0.144

Gnomad EAS AF: 0.167

Gnomad SAS AF: 0.238

Gnomad FIN AF: 0.249

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.207

Gnomad OTH AF: 0.149

GnomAD3 exomes AF: 0.190 AC: 47764 AN: 251310 Hom.: 4978 AF XY: 0.194 AC XY: 26385 AN XY: 135832

Gnomad AFR exome AF: 0.0349

Gnomad AMR exome AF: 0.174

Gnomad ASJ exome AF: 0.139

Gnomad EAS exome AF: 0.166

Gnomad SAS exome AF: 0.237

Gnomad FIN exome AF: 0.245

Gnomad NFE exome AF: 0.203

Gnomad OTH exome AF: 0.183

GnomAD4 exome AF: 0.201 AC: 293494 AN: 1461216 Hom.: 30350 Cov.: 34 AF XY: 0.202 AC XY: 146768 AN XY: 726944

Gnomad4 AFR exome AF: 0.0306

Gnomad4 AMR exome AF: 0.174

Gnomad4 ASJ exome AF: 0.143

Gnomad4 EAS exome AF: 0.180

Gnomad4 SAS exome AF: 0.238

Gnomad4 FIN exome AF: 0.238

Gnomad4 NFE exome AF: 0.206

Gnomad4 OTH exome AF: 0.181

GnomAD4 genome AF: 0.156 AC: 23709 AN: 152260 Hom.: 2284 Cov.: 33 AF XY: 0.158 AC XY: 11734 AN XY: 74448

Gnomad4 AFR AF: 0.0423

Gnomad4 AMR AF: 0.148

Gnomad4 ASJ AF: 0.144

Gnomad4 EAS AF: 0.168

Gnomad4 SAS AF: 0.237

Gnomad4 FIN AF: 0.249

Gnomad4 NFE AF: 0.207

Gnomad4 OTH AF: 0.155

Alfa AF: 0.186 Hom.: 5585

Bravo AF: 0.140

Asia WGS AF: 0.210 AC: 732 AN: 3478

EpiCase AF: 0.190

EpiControl AF: 0.186

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Laryngo-onycho-cutaneous syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -

Junctional epidermolysis bullosa gravis of Herlitz Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -

Junctional epidermolysis bullosa, non-Herlitz type Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	5.3
DANN	Benign	0.82

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: rs1131521; hg19: chr18-21513768; COSMIC: COSV52530854; COSMIC: COSV52530854;