rs77331026

chr18-23857953-G-Achr18-23857953-G-Cchr18-23857953-G-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2 BP4_Strong BP6 BS1

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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1416L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00013 (1 hom.)
• Consequence: LAMA3 NM_198129.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 2.33

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 -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. This position pass quality control queck.

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMA3	ENST00000313654.14	c.4246G>A	p.Val1416Met	missense_variant	33/75	1	NM_198129.4	P1
LAMA3	ENST00000399516.7	c.4246G>A	p.Val1416Met	missense_variant	33/74	1
LAMA3	ENST00000649721.1	c.1138G>A	p.Val380Met	missense_variant	8/48

Frequencies

GnomAD3 genomes AF: 0.00120 AC: 182 AN: 152210 Hom.: 0 Cov.: 33

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: 72 AN: 249568 Hom.: 0 AF XY: 0.000251 AC XY: 34 AN XY: 135404

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.: 1 Cov.: 32 AF XY: 0.000121 AC XY: 88 AN XY: 727228

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.: 0 Cov.: 33 AF XY: 0.00109 AC XY: 81 AN XY: 74494

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.: 0

Bravo AF: 0.00131

ESP6500AA AF: 0.00487 AC: 20

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000331 AC: 40

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

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

Invitae

May 27, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.22
Cadd	Benign	23
Dann	Pathogenic	1.0
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.84	D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.022	T;T;T
MetaSVM	Benign	-0.42	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.37	T
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	T
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

Other links and lift over

dbSNP: rs77331026; hg19: chr18-21437917;