rs774133746

Positions:

• chr18-23928148-C-G
• chr18-23928148-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_198129.4(LAMA3):​c.8203C>G​(p.Arg2735Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: LAMA3 NM_198129.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.66

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.842

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMA3	NM_198129.4	c.8203C>G	p.Arg2735Gly	missense_variant	63/75	ENST00000313654.14	NP_937762.2
LAMA3	NM_000227.6	c.3376C>G	p.Arg1126Gly	missense_variant	26/38	ENST00000269217.11	NP_000218.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAMA3	ENST00000313654.14	c.8203C>G	p.Arg2735Gly	missense_variant	63/75	1	NM_198129.4	ENSP00000324532	P1
LAMA3	ENST00000269217.11	c.3376C>G	p.Arg1126Gly	missense_variant	26/38	1	NM_000227.6	ENSP00000269217

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.065	.;T;.;.;.
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.89	.;D;D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.84	D;D;D;D;D
MetaSVM	Uncertain	0.32	D
MutationTaster	Benign	0.80	D;D;D;D
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-4.9	D;D;.;D;.
REVEL	Uncertain	0.64
Sift	Uncertain	0.0030	D;D;.;D;.
Sift4G	Uncertain	0.0050	.;.;.;D;D
Vest4		0.71
MutPred		0.66		Loss of MoRF binding (P = 0.0023);.;.;.;.;
MVP		0.89
MPC		0.62
ClinPred		0.99	D
GERP RS		5.8
gMVP		0.83

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: rs774133746; hg19: chr18-21508112;