18-23931070-C-A

Position:

• chr18-23931070-C-A

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.8445C>A​(p.Asn2815Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.198 in 1,610,202 control chromosomes in the GnomAD database, including 32,847 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. N2815N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.16 (2357 hom., cov: 32)
  • Exomes 𝑓: 0.20 (30490 hom.)
• Consequence: LAMA3 NM_198129.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.0170

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 (MetaRNN=0.0017926991).
• BP6: Variant 18-23931070-C-A is Benign according to our data. Variant chr18-23931070-C-A is described in ClinVar as [Benign]. Clinvar id is 255575.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.225 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMA3	NM_198129.4	c.8445C>A	p.Asn2815Lys	missense_variant	65/75	ENST00000313654.14
LAMA3	NM_000227.6	c.3618C>A	p.Asn1206Lys	missense_variant	28/38	ENST00000269217.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMA3	ENST00000313654.14	c.8445C>A	p.Asn2815Lys	missense_variant	65/75	1	NM_198129.4	P1
LAMA3	ENST00000269217.11	c.3618C>A	p.Asn1206Lys	missense_variant	28/38	1	NM_000227.6

Frequencies

GnomAD3 genomes AF: 0.162 AC: 24679 AN: 151974 Hom.: 2350 Cov.: 32

Gnomad AFR AF: 0.0629

Gnomad AMI AF: 0.0855

Gnomad AMR AF: 0.151

Gnomad ASJ AF: 0.144

Gnomad EAS AF: 0.166

Gnomad SAS AF: 0.238

Gnomad FIN AF: 0.257

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.208

Gnomad OTH AF: 0.153

GnomAD3 exomes AF: 0.192 AC: 48334 AN: 251140 Hom.: 5066 AF XY: 0.196 AC XY: 26637 AN XY: 135712

Gnomad AFR exome AF: 0.0571

Gnomad AMR exome AF: 0.174

Gnomad ASJ exome AF: 0.140

Gnomad EAS exome AF: 0.166

Gnomad SAS exome AF: 0.237

Gnomad FIN exome AF: 0.251

Gnomad NFE exome AF: 0.203

Gnomad OTH exome AF: 0.185

GnomAD4 exome AF: 0.201 AC: 293404 AN: 1458110 Hom.: 30490 Cov.: 31 AF XY: 0.202 AC XY: 146758 AN XY: 725554

Gnomad4 AFR exome AF: 0.0521

Gnomad4 AMR exome AF: 0.175

Gnomad4 ASJ exome AF: 0.144

Gnomad4 EAS exome AF: 0.179

Gnomad4 SAS exome AF: 0.238

Gnomad4 FIN exome AF: 0.245

Gnomad4 NFE exome AF: 0.205

Gnomad4 OTH exome AF: 0.182

GnomAD4 genome AF: 0.162 AC: 24696 AN: 152092 Hom.: 2357 Cov.: 32 AF XY: 0.164 AC XY: 12202 AN XY: 74336

Gnomad4 AFR AF: 0.0628

Gnomad4 AMR AF: 0.151

Gnomad4 ASJ AF: 0.144

Gnomad4 EAS AF: 0.167

Gnomad4 SAS AF: 0.237

Gnomad4 FIN AF: 0.257

Gnomad4 NFE AF: 0.208

Gnomad4 OTH AF: 0.159

Alfa AF: 0.187 Hom.: 6641

Bravo AF: 0.147

TwinsUK AF: 0.219 AC: 811

ALSPAC AF: 0.206 AC: 793

ESP6500AA AF: 0.0622 AC: 274

ESP6500EA AF: 0.199 AC: 1711

ExAC AF: 0.189 AC: 22908

Asia WGS AF: 0.211 AC: 733 AN: 3478

EpiCase AF: 0.190

EpiControl AF: 0.186

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 16, 2019	Variant summary: LAMA3 c.3618C>A (p.Asn1206Lys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.19 in 251140 control chromosomes, predominantly at a frequency of 0.24 within the South Asian subpopulation in the gnomAD database, including 894 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 531 fold of the estimated maximal expected allele frequency for a pathogenic variant in LAMA3 causing Junctional Epidermolysis Bullosa phenotype (0.00045), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.3618C>A has been reported in the literature in individuals affected with atopic dermatitis and also in the control population (Stemmler_2014). This report does not provide unequivocal conclusions about association of the variant with Junctional Epidermolysis Bullosa . To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

not provided Benign:3

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

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
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	8.3
DANN	Benign	0.91
DEOGEN2	Benign	0.017	.;T;.;.;.;T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.51	.;T;T;T;T;T
MetaRNN	Benign	0.0018	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.7e-15	P;P;P;P
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.43	N;N;.;N;.;.
REVEL	Benign	0.16
Sift	Benign	0.23	T;T;.;T;.;.
Sift4G	Benign	0.25	.;.;.;T;T;T
Vest4		0.047
MutPred		0.53		Gain of ubiquitination at N2815 (P = 0.0311);.;.;.;.;.;
MPC		0.14
ClinPred		0.0015	T
GERP RS		2.6
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1154232; hg19: chr18-21511034; COSMIC: COSV52530831; COSMIC: COSV52530831;