18-23901269-C-G

Position:

• chr18-23901269-C-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_198129.4(LAMA3):​c.6147C>G​(p.Ala2049Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.256 in 1,613,664 control chromosomes in the GnomAD database, including 55,712 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3841 hom., cov: 32)
  • Exomes 𝑓: 0.26 (51871 hom.)
• Consequence: LAMA3 NM_198129.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.587

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 18-23901269-C-G is Benign according to our data. Variant chr18-23901269-C-G is described in ClinVar as [Benign]. Clinvar id is 255573.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.587 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.272 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMA3	NM_198129.4	c.6147C>G	p.Ala2049Ala	synonymous_variant	48/75	ENST00000313654.14	NP_937762.2
LAMA3	NM_000227.6	c.1320C>G	p.Ala440Ala	synonymous_variant	11/38	ENST00000269217.11	NP_000218.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAMA3	ENST00000313654.14	c.6147C>G	p.Ala2049Ala	synonymous_variant	48/75	1	NM_198129.4	ENSP00000324532.8
LAMA3	ENST00000269217.11	c.1320C>G	p.Ala440Ala	synonymous_variant	11/38	1	NM_000227.6	ENSP00000269217.5

Frequencies

GnomAD3 genomes AF: 0.202 AC: 30705 AN: 152032 Hom.: 3833 Cov.: 32

Gnomad AFR AF: 0.0542

Gnomad AMI AF: 0.111

Gnomad AMR AF: 0.187

Gnomad ASJ AF: 0.196

Gnomad EAS AF: 0.174

Gnomad SAS AF: 0.254

Gnomad FIN AF: 0.333

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.276

Gnomad OTH AF: 0.192

GnomAD3 exomes AF: 0.237 AC: 59678 AN: 251306 Hom.: 7799 AF XY: 0.243 AC XY: 32959 AN XY: 135806

Gnomad AFR exome AF: 0.0459

Gnomad AMR exome AF: 0.196

Gnomad ASJ exome AF: 0.189

Gnomad EAS exome AF: 0.169

Gnomad SAS exome AF: 0.256

Gnomad FIN exome AF: 0.320

Gnomad NFE exome AF: 0.272

Gnomad OTH exome AF: 0.233

GnomAD4 exome AF: 0.262 AC: 382613 AN: 1461514 Hom.: 51871 Cov.: 36 AF XY: 0.262 AC XY: 190603 AN XY: 727062

Gnomad4 AFR exome AF: 0.0407

Gnomad4 AMR exome AF: 0.199

Gnomad4 ASJ exome AF: 0.190

Gnomad4 EAS exome AF: 0.190

Gnomad4 SAS exome AF: 0.257

Gnomad4 FIN exome AF: 0.315

Gnomad4 NFE exome AF: 0.275

Gnomad4 OTH exome AF: 0.235

GnomAD4 genome AF: 0.202 AC: 30716 AN: 152150 Hom.: 3841 Cov.: 32 AF XY: 0.203 AC XY: 15098 AN XY: 74338

Gnomad4 AFR AF: 0.0540

Gnomad4 AMR AF: 0.187

Gnomad4 ASJ AF: 0.196

Gnomad4 EAS AF: 0.174

Gnomad4 SAS AF: 0.253

Gnomad4 FIN AF: 0.333

Gnomad4 NFE AF: 0.276

Gnomad4 OTH AF: 0.198

Alfa AF: 0.167 Hom.: 487

Bravo AF: 0.181

Asia WGS AF: 0.219 AC: 764 AN: 3478

EpiCase AF: 0.258

EpiControl AF: 0.250

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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	-	- -

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	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

Junctional epidermolysis bullosa gravis of Herlitz Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

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	-0.52
CADD	Benign	3.7
DANN	Benign	0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs1154226; hg19: chr18-21481233; COSMIC: COSV52530814; COSMIC: COSV52530814;