18-23689936-G-A

Variant names:

• chr18-23689936-G-A
• NM_198129.4:c.253G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_198129.4(LAMA3):​c.253G>A​(p.Val85Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000364 in 1,373,238 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: LAMA3 NM_198129.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.72

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31367958).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMA3	NM_198129.4	c.253G>A	p.Val85Ile	missense_variant	Exon 1 of 75	ENST00000313654.14	NP_937762.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMA3	ENST00000313654.14	c.253G>A	p.Val85Ile	missense_variant	Exon 1 of 75	1	NM_198129.4	ENSP00000324532.8
LAMA3	ENST00000399516.7	c.253G>A	p.Val85Ile	missense_variant	Exon 1 of 74	1		ENSP00000382432.2
LAMA3	ENST00000585600.5	n.253G>A		non_coding_transcript_exon_variant	Exon 1 of 13	1		ENSP00000468316.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000364 AC: 5 AN: 1373238 Hom.: 0 Cov.: 31 AF XY: 0.00000296 AC XY: 2 AN XY: 676446

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000601

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000281

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Feb 05, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.253G>A (p.V85I) alteration is located in exon 1 (coding exon 1) of the LAMA3 gene. This alteration results from a G to A substitution at nucleotide position 253, causing the valine (V) at amino acid position 85 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.046	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.017	.;T
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.96	.;D
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.31	T;T
MetaSVM	Uncertain	0.37	D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.60	N;N
REVEL	Uncertain	0.48
Sift	Uncertain	0.011	D;D
Vest4		0.30
MutPred		0.55		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP		0.67
MPC		2.4
ClinPred		0.88	D
GERP RS		4.2
gMVP		0.13

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr18-21269900;