18-23689960-A-G

Variant names:

• chr18-23689960-A-G
• rs2060548460
• NM_198129.4:c.277A>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_198129.4(LAMA3):​c.277A>G​(p.Ser93Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LAMA3 NM_198129.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.942

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10386774).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMA3	NM_198129.4	c.277A>G	p.Ser93Gly	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.277A>G	p.Ser93Gly	missense_variant	Exon 1 of 75	1	NM_198129.4	ENSP00000324532.8
LAMA3	ENST00000399516.7	c.277A>G	p.Ser93Gly	missense_variant	Exon 1 of 74	1		ENSP00000382432.2
LAMA3	ENST00000585600.5	n.277A>G		non_coding_transcript_exon_variant	Exon 1 of 13	1		ENSP00000468316.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1363742 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 670956

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jul 30, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.277A>G (p.S93G) alteration is located in exon 1 (coding exon 1) of the LAMA3 gene. This alteration results from a A to G substitution at nucleotide position 277, causing the serine (S) at amino acid position 93 to be replaced by a glycine (G). 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	0.063
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.029	.;T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.62	.;T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.10	T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.031
Sift	Benign	0.36	T;T
Vest4		0.10
MutPred		0.45		Loss of glycosylation at S93 (P = 0.0177);Loss of glycosylation at S93 (P = 0.0177);
MVP		0.21
MPC		1.8
ClinPred		0.11	T
GERP RS		1.6
gMVP		0.14

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: rs2060548460; hg19: chr18-21269924;