rs2241643

Positions:

chr18-23949758-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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. 3/3 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:10

Conservation

PhyloP100: -0.989

Variant links:

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]

LAMA3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 linkuse as main transcript	c.4525-7G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000269217.11
LAMA3	NM_198129.4 linkuse as main transcript	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 linkuse as main transcript	c.4525-7G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000227.6		Q16787-1
LAMA3	ENST00000313654.14 linkuse as main transcript	c.9352-7G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_198129.4	P1	Q16787-2

Frequencies

GnomAD3 genomes

AF:

0.514

AC:

77894

AN:

151606

Hom.:

22827

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.622

AC XY:

451801

AN XY:

726762

show subpopulations

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.:

AF XY:

0.505

AC XY:

37473

AN XY:

74148

show subpopulations

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:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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	- -

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

-0.78

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over