18-23689762-C-A

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.79C>A(p.Arg27=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000939 in 1,523,092 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0051 (8 hom., cov: 32)
  • Exomes 𝑓: 0.00048 (8 hom.)
• Consequence: LAMA3 NM_198129.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.499

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=-0.54).
• BP6: Variant 18-23689762-C-A is Benign according to our data. Variant chr18-23689762-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 1710791.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.499 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0051 (777/152258) while in subpopulation AFR AF= 0.0179 (745/41570). AF 95% confidence interval is 0.0169. There are 8 homozygotes in gnomad4. There are 386 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMA3	NM_198129.4	c.79C>A	p.Arg27=	synonymous_variant	1/75	ENST00000313654.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMA3	ENST00000313654.14	c.79C>A	p.Arg27=	synonymous_variant	1/75	1	NM_198129.4	P1
LAMA3	ENST00000399516.7	c.79C>A	p.Arg27=	synonymous_variant	1/74	1
LAMA3	ENST00000585600.5	c.79C>A	p.Arg27=	synonymous_variant	1/13	1

Frequencies

GnomAD3 genomes AF: 0.00506 AC: 770 AN: 152144 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0178

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.000578 AC: 67 AN: 115992 Hom.: 0 AF XY: 0.000452 AC XY: 29 AN XY: 64136

Gnomad AFR exome AF: 0.0173

Gnomad AMR exome AF: 0.000662

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000497

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000477

Gnomad OTH exome AF: 0.000289

GnomAD4 exome AF: 0.000476 AC: 653 AN: 1370834 Hom.: 8 Cov.: 31 AF XY: 0.000459 AC XY: 310 AN XY: 675578

Gnomad4 AFR exome AF: 0.0192

Gnomad4 AMR exome AF: 0.000754

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000302

Gnomad4 SAS exome AF: 0.0000261

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000841

Gnomad4 OTH exome AF: 0.00116

GnomAD4 genome AF: 0.00510 AC: 777 AN: 152258 Hom.: 8 Cov.: 32 AF XY: 0.00519 AC XY: 386 AN XY: 74428

Gnomad4 AFR AF: 0.0179

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00243 Hom.: 0

Bravo AF: 0.00558

Asia WGS AF: 0.00144 AC: 5 AN: 3476

ClinVar

Significance: Benign/Likely 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	Invitae	Jul 05, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 16, 2022	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
Cadd	Benign	7.5
Dann	Benign	0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs371129898; hg19: chr18-21269726;