18-23714058-T-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_198129.4(LAMA3):c.433T>C(p.Leu145=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00143 in 1,614,022 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0072 (10 hom., cov: 30)
  • Exomes 𝑓: 0.00082 (12 hom.)
• Consequence: LAMA3 NM_198129.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.546

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 18-23714058-T-C is Benign according to our data. Variant chr18-23714058-T-C is described in ClinVar as [Benign]. Clinvar id is 1666850.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.546 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00722 (1098/152152) while in subpopulation AFR AF= 0.0247 (1026/41476). AF 95% confidence interval is 0.0235. There are 10 homozygotes in gnomad4. There are 495 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMA3	NM_198129.4	c.433T>C	p.Leu145=	synonymous_variant	2/75	ENST00000313654.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMA3	ENST00000313654.14	c.433T>C	p.Leu145=	synonymous_variant	2/75	1	NM_198129.4	P1
LAMA3	ENST00000399516.7	c.433T>C	p.Leu145=	synonymous_variant	2/74	1
LAMA3	ENST00000585600.5	c.433T>C	p.Leu145=	synonymous_variant	2/13	1

Frequencies

GnomAD3 genomes AF: 0.00722 AC: 1097 AN: 152034 Hom.: 10 Cov.: 30

Gnomad AFR AF: 0.0248

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00575

GnomAD3 exomes AF: 0.00200 AC: 500 AN: 249504 Hom.: 7 AF XY: 0.00160 AC XY: 217 AN XY: 135368

Gnomad AFR exome AF: 0.0266

Gnomad AMR exome AF: 0.00162

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000177

Gnomad OTH exome AF: 0.00149

GnomAD4 exome AF: 0.000823 AC: 1203 AN: 1461870 Hom.: 12 Cov.: 34 AF XY: 0.000732 AC XY: 532 AN XY: 727240

Gnomad4 AFR exome AF: 0.0257

Gnomad4 AMR exome AF: 0.00177

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000121

Gnomad4 OTH exome AF: 0.00200

GnomAD4 genome AF: 0.00722 AC: 1098 AN: 152152 Hom.: 10 Cov.: 30 AF XY: 0.00665 AC XY: 495 AN XY: 74392

Gnomad4 AFR AF: 0.0247

Gnomad4 AMR AF: 0.00307

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00569

Alfa AF: 0.00402 Hom.: 5

Bravo AF: 0.00865

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 03, 2022

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
Cadd	Benign	7.1
Dann	Benign	0.77

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: rs115800115; hg19: chr18-21294022;