18-23689740-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_198129.4(LAMA3):c.57G>C(p.Thr19=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0182 in 1,494,962 control chromosomes in the GnomAD database, including 372 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (34 hom., cov: 32)
  • Exomes 𝑓: 0.018 (338 hom.)
• Consequence: LAMA3 NM_198129.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.621

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=-0.65).
• BP6: Variant 18-23689740-G-C is Benign according to our data. Variant chr18-23689740-G-C is described in ClinVar as [Benign]. Clinvar id is 1166874.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-23689740-G-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.621 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0156 (2367/152208) while in subpopulation NFE AF= 0.0213 (1450/67980). AF 95% confidence interval is 0.0204. There are 34 homozygotes in gnomad4. There are 1214 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 34 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMA3	NM_198129.4	c.57G>C	p.Thr19=	synonymous_variant	1/75	ENST00000313654.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMA3	ENST00000313654.14	c.57G>C	p.Thr19=	synonymous_variant	1/75	1	NM_198129.4	P1
LAMA3	ENST00000399516.7	c.57G>C	p.Thr19=	synonymous_variant	1/74	1
LAMA3	ENST00000585600.5	c.57G>C	p.Thr19=	synonymous_variant	1/13	1

Frequencies

GnomAD3 genomes AF: 0.0156 AC: 2367 AN: 152096 Hom.: 34 Cov.: 32

Gnomad AFR AF: 0.00350

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.00733

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00724

Gnomad FIN AF: 0.0509

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0213

Gnomad OTH AF: 0.0163

GnomAD3 exomes AF: 0.0137 AC: 1308 AN: 95200 Hom.: 23 AF XY: 0.0138 AC XY: 734 AN XY: 53130

Gnomad AFR exome AF: 0.00312

Gnomad AMR exome AF: 0.00330

Gnomad ASJ exome AF: 0.00615

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00805

Gnomad FIN exome AF: 0.0488

Gnomad NFE exome AF: 0.0199

Gnomad OTH exome AF: 0.0117

GnomAD4 exome AF: 0.0185 AC: 24832 AN: 1342754 Hom.: 338 Cov.: 31 AF XY: 0.0186 AC XY: 12283 AN XY: 660098

Gnomad4 AFR exome AF: 0.00201

Gnomad4 AMR exome AF: 0.00390

Gnomad4 ASJ exome AF: 0.00688

Gnomad4 EAS exome AF: 0.0000976

Gnomad4 SAS exome AF: 0.00898

Gnomad4 FIN exome AF: 0.0515

Gnomad4 NFE exome AF: 0.0200

Gnomad4 OTH exome AF: 0.0137

GnomAD4 genome AF: 0.0156 AC: 2367 AN: 152208 Hom.: 34 Cov.: 32 AF XY: 0.0163 AC XY: 1214 AN XY: 74426

Gnomad4 AFR AF: 0.00349

Gnomad4 AMR AF: 0.00732

Gnomad4 ASJ AF: 0.0104

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00724

Gnomad4 FIN AF: 0.0509

Gnomad4 NFE AF: 0.0213

Gnomad4 OTH AF: 0.0161

Alfa AF: 0.0185 Hom.: 14

Bravo AF: 0.0113

Asia WGS AF: 0.00318 AC: 11 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Sep 12, 2022	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
Cadd	Benign	6.6
Dann	Benign	0.84

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: rs61752345; hg19: chr18-21269704;