rs2288592

Positions:

• chr18-23946123-C-T

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.9211-21C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.612 in 1,607,248 control chromosomes in the GnomAD database, including 317,497 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (22805 hom., cov: 30)
  • Exomes 𝑓: 0.62 (294692 hom.)
• Consequence: LAMA3 NM_198129.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.09

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=-0.9).
• BP6: Variant 18-23946123-C-T is Benign according to our data. Variant chr18-23946123-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 255579.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.668 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMA3	NM_000227.6	c.4384-21C>T		intron_variant		ENST00000269217.11
LAMA3	NM_198129.4	c.9211-21C>T		intron_variant		ENST00000313654.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMA3	ENST00000269217.11	c.4384-21C>T		intron_variant		1	NM_000227.6
LAMA3	ENST00000313654.14	c.9211-21C>T		intron_variant		1	NM_198129.4	P1

Frequencies

GnomAD3 genomes AF: 0.514 AC: 78049 AN: 151742 Hom.: 22806 Cov.: 30

Gnomad AFR AF: 0.268

Gnomad AMI AF: 0.707

Gnomad AMR AF: 0.484

Gnomad ASJ AF: 0.704

Gnomad EAS AF: 0.162

Gnomad SAS AF: 0.410

Gnomad FIN AF: 0.627

Gnomad MID AF: 0.596

Gnomad NFE AF: 0.674

Gnomad OTH AF: 0.551

GnomAD3 exomes AF: 0.534 AC: 134214 AN: 251384 Hom.: 40055 AF XY: 0.546 AC XY: 74132 AN XY: 135862

Gnomad AFR exome AF: 0.257

Gnomad AMR exome AF: 0.373

Gnomad ASJ exome AF: 0.700

Gnomad EAS exome AF: 0.165

Gnomad SAS exome AF: 0.428

Gnomad FIN exome AF: 0.625

Gnomad NFE exome AF: 0.675

Gnomad OTH exome AF: 0.604

GnomAD4 exome AF: 0.622 AC: 905897 AN: 1455388 Hom.: 294692 Cov.: 33 AF XY: 0.620 AC XY: 449067 AN XY: 724342

Gnomad4 AFR exome AF: 0.251

Gnomad4 AMR exome AF: 0.388

Gnomad4 ASJ exome AF: 0.699

Gnomad4 EAS exome AF: 0.138

Gnomad4 SAS exome AF: 0.426

Gnomad4 FIN exome AF: 0.633

Gnomad4 NFE exome AF: 0.675

Gnomad4 OTH exome AF: 0.598

GnomAD4 genome AF: 0.514 AC: 78061 AN: 151860 Hom.: 22805 Cov.: 30 AF XY: 0.506 AC XY: 37533 AN XY: 74238

Gnomad4 AFR AF: 0.268

Gnomad4 AMR AF: 0.484

Gnomad4 ASJ AF: 0.704

Gnomad4 EAS AF: 0.162

Gnomad4 SAS AF: 0.410

Gnomad4 FIN AF: 0.627

Gnomad4 NFE AF: 0.674

Gnomad4 OTH AF: 0.546

Alfa AF: 0.650 Hom.: 55381

Bravo AF: 0.493

Asia WGS AF: 0.285 AC: 991 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Junctional epidermolysis bullosa, non-Herlitz type Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Laryngo-onycho-cutaneous syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Junctional epidermolysis bullosa gravis of Herlitz Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.057
DANN	Benign	0.53

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: rs2288592; hg19: chr18-21526087; COSMIC: COSV52531938; COSMIC: COSV52531938;