rs2241643

chr18-23949758-G-A

Variant summary

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

The NM_198129.4(LAMA3):c.9352-7G>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.614 in 1,612,626 control chromosomes in the GnomAD database, including 319,876 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (22825 hom., cov: 30)
  • Exomes 𝑓: 0.62 (297051 hom.)
• Consequence: LAMA3 NM_198129.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00005356
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.989

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 18-23949758-G-A is Benign according to our data. Variant chr18-23949758-G-A is described in ClinVar as [Benign]. Clinvar id is 255580.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-23949758-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.67 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMA3	NM_000227.6	c.4525-7G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000269217.11
LAMA3	NM_198129.4	c.9352-7G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000313654.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMA3	ENST00000269217.11	c.4525-7G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000227.6
LAMA3	ENST00000313654.14	c.9352-7G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_198129.4	P1

Frequencies

GnomAD3 genomes AF: 0.514 AC: 77894 AN: 151606 Hom.: 22827 Cov.: 30

Gnomad AFR AF: 0.261

Gnomad AMI AF: 0.703

Gnomad AMR AF: 0.484

Gnomad ASJ AF: 0.705

Gnomad EAS AF: 0.162

Gnomad SAS AF: 0.415

Gnomad FIN AF: 0.636

Gnomad MID AF: 0.596

Gnomad NFE AF: 0.675

Gnomad OTH AF: 0.551

GnomAD3 exomes AF: 0.535 AC: 134519 AN: 251304 Hom.: 40258 AF XY: 0.547 AC XY: 74340 AN XY: 135838

Gnomad AFR exome AF: 0.251

Gnomad AMR exome AF: 0.373

Gnomad ASJ exome AF: 0.700

Gnomad EAS exome AF: 0.165

Gnomad SAS exome AF: 0.433

Gnomad FIN exome AF: 0.631

Gnomad NFE exome AF: 0.676

Gnomad OTH exome AF: 0.605

GnomAD4 exome AF: 0.624 AC: 911763 AN: 1460902 Hom.: 297051 Cov.: 44 AF XY: 0.622 AC XY: 451801 AN XY: 726762

Gnomad4 AFR exome AF: 0.247

Gnomad4 AMR exome AF: 0.387

Gnomad4 ASJ exome AF: 0.699

Gnomad4 EAS exome AF: 0.138

Gnomad4 SAS exome AF: 0.430

Gnomad4 FIN exome AF: 0.640

Gnomad4 NFE exome AF: 0.676

Gnomad4 OTH exome AF: 0.600

GnomAD4 genome AF: 0.513 AC: 77900 AN: 151724 Hom.: 22825 Cov.: 30 AF XY: 0.505 AC XY: 37473 AN XY: 74148

Gnomad4 AFR AF: 0.260

Gnomad4 AMR AF: 0.484

Gnomad4 ASJ AF: 0.705

Gnomad4 EAS AF: 0.162

Gnomad4 SAS AF: 0.415

Gnomad4 FIN AF: 0.636

Gnomad4 NFE AF: 0.675

Gnomad4 OTH AF: 0.545

Alfa AF: 0.643 Hom.: 41291

Bravo AF: 0.492

Asia WGS AF: 0.288 AC: 1002 AN: 3478

EpiCase AF: 0.688

EpiControl AF: 0.686

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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 -

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	Genome-Nilou Lab	Jul 10, 2021	- -
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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

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	-0.78
Cadd	Benign	0.95
Dann	Benign	0.47

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000054
dbscSNV1_RF	Benign	0.016
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: rs2241643; hg19: chr18-21529722; COSMIC: COSV52532000; COSMIC: COSV52532000;