18-23890029-C-T

Position:

• chr18-23890029-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_198129.4(LAMA3):​c.5322C>T​(p.Phe1774=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0369 in 1,613,238 control chromosomes in the GnomAD database, including 3,839 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.082 (1064 hom., cov: 32)
  • Exomes 𝑓: 0.032 (2775 hom.)
• Consequence: LAMA3 NM_198129.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.939

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.3).
• BP6: Variant 18-23890029-C-T is Benign according to our data. Variant chr18-23890029-C-T is described in ClinVar as [Benign]. Clinvar id is 255581.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.939 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.181 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMA3	NM_198129.4	c.5322C>T	p.Phe1774=	synonymous_variant	42/75	ENST00000313654.14	NP_937762.2
LAMA3	NM_000227.6	c.495C>T	p.Phe165=	synonymous_variant	5/38	ENST00000269217.11	NP_000218.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAMA3	ENST00000313654.14	c.5322C>T	p.Phe1774=	synonymous_variant	42/75	1	NM_198129.4	ENSP00000324532	P1
LAMA3	ENST00000269217.11	c.495C>T	p.Phe165=	synonymous_variant	5/38	1	NM_000227.6	ENSP00000269217

Frequencies

GnomAD3 genomes AF: 0.0817 AC: 12430 AN: 152064 Hom.: 1055 Cov.: 32

Gnomad AFR AF: 0.184

Gnomad AMI AF: 0.119

Gnomad AMR AF: 0.177

Gnomad ASJ AF: 0.0107

Gnomad EAS AF: 0.0652

Gnomad SAS AF: 0.0425

Gnomad FIN AF: 0.0153

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0166

Gnomad OTH AF: 0.0632

GnomAD3 exomes AF: 0.0705 AC: 17717 AN: 251394 Hom.: 1809 AF XY: 0.0589 AC XY: 8001 AN XY: 135868

Gnomad AFR exome AF: 0.190

Gnomad AMR exome AF: 0.271

Gnomad ASJ exome AF: 0.0150

Gnomad EAS exome AF: 0.0607

Gnomad SAS exome AF: 0.0442

Gnomad FIN exome AF: 0.0195

Gnomad NFE exome AF: 0.0167

Gnomad OTH exome AF: 0.0503

GnomAD4 exome AF: 0.0322 AC: 47015 AN: 1461056 Hom.: 2775 Cov.: 31 AF XY: 0.0310 AC XY: 22506 AN XY: 726906

Gnomad4 AFR exome AF: 0.190

Gnomad4 AMR exome AF: 0.259

Gnomad4 ASJ exome AF: 0.0149

Gnomad4 EAS exome AF: 0.0686

Gnomad4 SAS exome AF: 0.0453

Gnomad4 FIN exome AF: 0.0213

Gnomad4 NFE exome AF: 0.0167

Gnomad4 OTH exome AF: 0.0385

GnomAD4 genome AF: 0.0820 AC: 12481 AN: 152182 Hom.: 1064 Cov.: 32 AF XY: 0.0838 AC XY: 6232 AN XY: 74392

Gnomad4 AFR AF: 0.184

Gnomad4 AMR AF: 0.178

Gnomad4 ASJ AF: 0.0107

Gnomad4 EAS AF: 0.0652

Gnomad4 SAS AF: 0.0433

Gnomad4 FIN AF: 0.0153

Gnomad4 NFE AF: 0.0166

Gnomad4 OTH AF: 0.0634

Alfa AF: 0.0432 Hom.: 176

Bravo AF: 0.101

Asia WGS AF: 0.0690 AC: 240 AN: 3478

EpiCase AF: 0.0146

EpiControl AF: 0.0159

ClinVar

Significance: Benign

Submissions summary: Benign:7

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	Nov 02, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Mar 04, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 16, 2019	Variant summary: LAMA3 c.495C>T alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.07 in 251394 control chromosomes, predominantly at a frequency of 0.27 within the Latino subpopulation in the gnomAD database, including 1412 homozygotes. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 597 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 Latino origin. To our knowledge, no occurrence of c.495C>T in individuals affected with Junctional Epidermolysis Bullosa and no experimental evidence demonstrating its impact on protein function have 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. -

Laryngo-onycho-cutaneous syndrome Benign:1

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. -

Junctional epidermolysis bullosa gravis of Herlitz Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.30
CADD	Benign	6.6
DANN	Benign	0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs958631; hg19: chr18-21469993; COSMIC: COSV52535427;