rs958631

Positions:

• chr18-23890029-C-G
• chr18-23890029-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_198129.4(LAMA3):​c.5322C>G​(p.Phe1774Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,444 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: LAMA3 NM_198129.4 missense
• Clinical Significance: Not reported in ClinVar
• 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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMA3	NM_198129.4	c.5322C>G	p.Phe1774Leu	missense_variant	42/75	ENST00000313654.14	NP_937762.2
LAMA3	NM_000227.6	c.495C>G	p.Phe165Leu	missense_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>G	p.Phe1774Leu	missense_variant	42/75	1	NM_198129.4	ENSP00000324532	P1
LAMA3	ENST00000269217.11	c.495C>G	p.Phe165Leu	missense_variant	5/38	1	NM_000227.6	ENSP00000269217

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251394 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135868

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461444 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727070

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Uncertain	0.044	T
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Benign	0.067	.;T;.;.;.
Eigen	Benign	0.14
Eigen_PC	Benign	0.0044
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.62	.;T;T;T;T
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.57	D;D;D;D;D
MetaSVM	Uncertain	-0.047	T
MutationTaster	Benign	0.00025	P;P;P;P
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-4.7	D;D;.;D;.
REVEL	Uncertain	0.45
Sift	Uncertain	0.0050	D;D;.;D;.
Sift4G	Uncertain	0.042	.;.;.;D;D
Vest4		0.63
MutPred		0.39		Gain of catalytic residue at F1774 (P = 0.292);Gain of catalytic residue at F1774 (P = 0.292);.;.;.;
MVP		0.68
MPC		0.61
ClinPred		0.99	D
GERP RS		-1.7
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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;