18-23861753-C-T

Position:

• chr18-23861753-C-T

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.4530C>T​(p.Pro1510=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.562 in 1,612,978 control chromosomes in the GnomAD database, including 267,823 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.47 (19028 hom., cov: 32)
  • Exomes 𝑓: 0.57 (248795 hom.)
• Consequence: LAMA3 NM_198129.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.50

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 18-23861753-C-T is Benign according to our data. Variant chr18-23861753-C-T is described in ClinVar as [Benign]. Clinvar id is 403027.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-23861753-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.51 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.611 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMA3	NM_198129.4	c.4530C>T	p.Pro1510=	synonymous_variant	35/75	ENST00000313654.14	NP_937762.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAMA3	ENST00000313654.14	c.4530C>T	p.Pro1510=	synonymous_variant	35/75	1	NM_198129.4	ENSP00000324532	P1
LAMA3	ENST00000399516.7	c.4530C>T	p.Pro1510=	synonymous_variant	35/74	1		ENSP00000382432
LAMA3	ENST00000649721.1	c.1422C>T	p.Pro474=	synonymous_variant	10/48			ENSP00000497885

Frequencies

GnomAD3 genomes AF: 0.470 AC: 71339 AN: 151876 Hom.: 19029 Cov.: 32

Gnomad AFR AF: 0.242

Gnomad AMI AF: 0.671

Gnomad AMR AF: 0.447

Gnomad ASJ AF: 0.659

Gnomad EAS AF: 0.161

Gnomad SAS AF: 0.397

Gnomad FIN AF: 0.548

Gnomad MID AF: 0.566

Gnomad NFE AF: 0.616

Gnomad OTH AF: 0.508

GnomAD3 exomes AF: 0.492 AC: 121982 AN: 247702 Hom.: 33211 AF XY: 0.502 AC XY: 67550 AN XY: 134448

Gnomad AFR exome AF: 0.234

Gnomad AMR exome AF: 0.352

Gnomad ASJ exome AF: 0.659

Gnomad EAS exome AF: 0.161

Gnomad SAS exome AF: 0.410

Gnomad FIN exome AF: 0.555

Gnomad NFE exome AF: 0.616

Gnomad OTH exome AF: 0.557

GnomAD4 exome AF: 0.572 AC: 835050 AN: 1460982 Hom.: 248795 Cov.: 54 AF XY: 0.569 AC XY: 413799 AN XY: 726726

Gnomad4 AFR exome AF: 0.229

Gnomad4 AMR exome AF: 0.364

Gnomad4 ASJ exome AF: 0.661

Gnomad4 EAS exome AF: 0.138

Gnomad4 SAS exome AF: 0.409

Gnomad4 FIN exome AF: 0.562

Gnomad4 NFE exome AF: 0.618

Gnomad4 OTH exome AF: 0.553

GnomAD4 genome AF: 0.469 AC: 71346 AN: 151996 Hom.: 19028 Cov.: 32 AF XY: 0.461 AC XY: 34255 AN XY: 74300

Gnomad4 AFR AF: 0.242

Gnomad4 AMR AF: 0.447

Gnomad4 ASJ AF: 0.659

Gnomad4 EAS AF: 0.162

Gnomad4 SAS AF: 0.397

Gnomad4 FIN AF: 0.548

Gnomad4 NFE AF: 0.616

Gnomad4 OTH AF: 0.503

Alfa AF: 0.598 Hom.: 37816

Bravo AF: 0.453

Asia WGS AF: 0.275 AC: 957 AN: 3478

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	GeneDx	Mar 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 13, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

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 -

Junctional epidermolysis bullosa, non-Herlitz type Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Laryngo-onycho-cutaneous syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Junctional epidermolysis bullosa gravis of Herlitz 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	-0.80
CADD	Benign	0.39
DANN	Benign	0.46

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: rs12965685; hg19: chr18-21441717; COSMIC: COSV58067121;