rs1555724108

Positions:

• chr18-23882044-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_198129.4(LAMA3):​c.5221A>G​(p.Ser1741Gly) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LAMA3 NM_198129.4 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.93

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
• PP5: Variant 18-23882044-A-G is Pathogenic according to our data. Variant chr18-23882044-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 550199.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMA3	NM_198129.4	c.5221A>G	p.Ser1741Gly	missense_variant, splice_region_variant	40/75	ENST00000313654.14	NP_937762.2
LAMA3	NM_000227.6	c.394A>G	p.Ser132Gly	missense_variant, splice_region_variant	3/38	ENST00000269217.11	NP_000218.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAMA3	ENST00000313654.14	c.5221A>G	p.Ser1741Gly	missense_variant, splice_region_variant	40/75	1	NM_198129.4	ENSP00000324532.8
LAMA3	ENST00000269217.11	c.394A>G	p.Ser132Gly	missense_variant, splice_region_variant	3/38	1	NM_000227.6	ENSP00000269217.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Junctional epidermolysis bullosa gravis of Herlitz Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Jan 11, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.030	.;T;.;.;.
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.75	.;T;T;T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.41	T;T;T;T;T
MetaSVM	Uncertain	-0.27	T
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.8	N;N;.;N;.
REVEL	Benign	0.27
Sift	Benign	0.047	D;T;.;D;.
Sift4G	Benign	0.062	.;.;.;T;T
Vest4		0.83
MutPred		0.58		Loss of stability (P = 0.0705);Loss of stability (P = 0.0705);.;.;.;
MVP		0.78
MPC		0.13
ClinPred		0.87	D
GERP RS		5.4
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.46		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.46		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555724108; hg19: chr18-21462008;