rs61752346

Positions:

• chr18-23933924-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_198129.4(LAMA3):​c.8851C>T​(p.Arg2951Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00247 in 1,614,022 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 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. R2951H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (10 hom.)
• Consequence: LAMA3 NM_198129.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: -0.284

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0075652897).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0014 (213/152280) while in subpopulation NFE AF= 0.00254 (173/68018). AF 95% confidence interval is 0.00223. There are 0 homozygotes in gnomad4. There are 82 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMA3	NM_198129.4	c.8851C>T	p.Arg2951Cys	missense_variant	67/75	ENST00000313654.14
LAMA3	NM_000227.6	c.4024C>T	p.Arg1342Cys	missense_variant	30/38	ENST00000269217.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMA3	ENST00000313654.14	c.8851C>T	p.Arg2951Cys	missense_variant	67/75	1	NM_198129.4	P1
LAMA3	ENST00000269217.11	c.4024C>T	p.Arg1342Cys	missense_variant	30/38	1	NM_000227.6

Frequencies

GnomAD3 genomes AF: 0.00140 AC: 213 AN: 152162 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000652

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00254

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00104 AC: 261 AN: 251434 Hom.: 0 AF XY: 0.00107 AC XY: 146 AN XY: 135890

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.000462

Gnomad NFE exome AF: 0.00201

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00258 AC: 3766 AN: 1461742 Hom.: 10 Cov.: 32 AF XY: 0.00242 AC XY: 1761 AN XY: 727178

Gnomad4 AFR exome AF: 0.000388

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000637

Gnomad4 NFE exome AF: 0.00326

Gnomad4 OTH exome AF: 0.00141

GnomAD4 genome AF: 0.00140 AC: 213 AN: 152280 Hom.: 0 Cov.: 32 AF XY: 0.00110 AC XY: 82 AN XY: 74474

Gnomad4 AFR AF: 0.000650

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00254

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00213 Hom.: 0

Bravo AF: 0.00153

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00302 AC: 26

ExAC AF: 0.000881 AC: 107

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00169

EpiControl AF: 0.00124

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Junctional epidermolysis bullosa gravis of Herlitz Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jan 05, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 07, 2022

Variant summary: LAMA3 c.4024C>T (p.Arg1342Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.001 in 251434 control chromosomes. The observed variant frequency is approximately 1.2 fold of the estimated maximal expected allele frequency for a pathogenic variant in LAMA3 causing Junctional Epidermolysis Bullosa phenotype (0.00087), strongly suggesting that the variant is benign. c.4024C>T has been reported in the literature as R1331C in at-least one individual affected with a mild clinical manifestation of Junctional Epidermolysis Bullosa with normal hemidesmosome by electron microscopy and normal Laminin 5 staining by immunofluorescence (example, Nakano_2002). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Laryngo-onycho-cutaneous syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	3.8
DANN	Benign	0.90
DEOGEN2	Benign	0.027	.;T;.;.;.
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.061	N
LIST_S2	Uncertain	0.89	.;D;D;D;D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.0076	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-1.4	N;N;.;N;.
REVEL	Benign	0.24
Sift	Benign	0.037	D;D;.;D;.
Sift4G	Benign	0.15	.;.;.;T;T
Vest4		0.17
MVP		0.15
MPC		0.27
ClinPred		0.015	T
GERP RS		1.0
gMVP		0.42

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: rs61752346; hg19: chr18-21513888; COSMIC: COSV52533639; COSMIC: COSV52533639;