chr18-23857953-G-A

Position:

chr18-23857953-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1

The NM_198129.4(LAMA3):c.4246G>A(p.Val1416Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000236 in 1,614,190 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00013 ( 1 hom. )

Consequence

LAMA3
NM_198129.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 2.33

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 -7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.02217108).

BP6

Variant 18-23857953-G-A is Benign according to our data. Variant chr18-23857953-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 587571.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00121 (184/152328) while in subpopulation AFR AF= 0.00409 (170/41572). AF 95% confidence interval is 0.00359. There are 0 homozygotes in gnomad4. There are 81 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMA3	NM_198129.4 link	c.4246G>A	p.Val1416Met	missense_variant	33/75	ENST00000313654.14	NP_937762.2	Q16787-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
LAMA3	ENST00000313654.14 link	c.4246G>A	p.Val1416Met	missense_variant	33/75	1	NM_198129.4	ENSP00000324532.8	Q16787-2
LAMA3	ENST00000399516.7 link	c.4246G>A	p.Val1416Met	missense_variant	33/74	1		ENSP00000382432.2	Q16787-3A0A0A0MSA0
LAMA3	ENST00000649721.1 link	c.1138G>A	p.Val380Met	missense_variant	8/48			ENSP00000497885.1	A0A3B3ITG1

Frequencies

GnomAD3 genomes

AF:

0.00120

AC:

182

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00405

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00192

GnomAD3 exomes

AF:

0.000288

AC:

AN:

249568

Hom.:

AF XY:

0.000251

AC XY:

AN XY:

135404

show subpopulations

Gnomad AFR exome

AF:

0.00400

Gnomad AMR exome

AF:

0.000203

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000111

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000135

AC:

197

AN:

1461862

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.00418

Gnomad4 AMR exome

AF:

0.000246

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.000513

GnomAD4 genome

AF:

0.00121

AC:

184

AN:

152328

Hom.:

Cov.:

AF XY:

0.00109

AC XY:

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.00409

Gnomad4 AMR

AF:

0.000261

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00190

Alfa

AF:

0.0000624

Hom.:

Bravo

AF:

0.00131

ESP6500AA

AF:

0.00487

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000331

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Junctional epidermolysis bullosa, non-Herlitz type

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Aug 07, 2018

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 27, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.058

.;T;.

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.65

.;T;T

M_CAP

Benign

0.027

MetaRNN

Benign

0.022

T;T;T

MetaSVM

Benign

-0.42

PrimateAI

Benign

0.37

PROVEAN

Uncertain

-2.5

D;D;.

REVEL

Benign

0.27

Sift

Uncertain

0.0040

D;D;.

Vest4

0.48

MVP

0.55

MPC

0.56

ClinPred

0.077

GERP RS

5.4

gMVP

0.70

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

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