18-23914539-A-T

Variant names:

• chr18-23914539-A-T
• rs1085308017
• NM_198129.4:c.7459A>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_198129.4(LAMA3):​c.7459A>T​(p.Met2487Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,864 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: LAMA3 NM_198129.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 3.16

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 18-23914539-A-T is Pathogenic according to our data. Variant chr18-23914539-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 427194.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMA3	NM_198129.4	c.7459A>T	p.Met2487Leu	missense_variant	Exon 57 of 75	ENST00000313654.14	NP_937762.2
LAMA3	NM_000227.6	c.2632A>T	p.Met878Leu	missense_variant	Exon 20 of 38	ENST00000269217.11	NP_000218.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMA3	ENST00000313654.14	c.7459A>T	p.Met2487Leu	missense_variant	Exon 57 of 75	1	NM_198129.4	ENSP00000324532.8
LAMA3	ENST00000269217.11	c.2632A>T	p.Met878Leu	missense_variant	Exon 20 of 38	1	NM_000227.6	ENSP00000269217.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251276 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135810

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461864 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727232

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: 0.00000809

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Apr 14, 2015

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.M878L variant in the LAMA3 gene has been published as a JEB pathogenic variant, however the reported study is of this same individual reported by another laboratory.(Varki et al 2007) The p.M878L variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The p.M878L variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. The p.M878L variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across class. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. No nearby missense variants in nearby residues have been reported in the Human Gene Mutation Database. The p.M878L variant is a strong candidate for a disease-causing variant, however the possibility it may be a rare benign variant cannot be excluded. -

Junctional epidermolysis bullosa gravis of Herlitz Uncertain:1

Feb 27, 2017

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.019	.;T;.;.;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.79	.;T;T;T;T
M_CAP	Benign	0.028	D
MetaRNN	Uncertain	0.58	D;D;D;D;D
MetaSVM	Benign	-0.38	T
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.4	N;N;.;N;.
REVEL	Uncertain	0.33
Sift	Benign	0.046	D;T;.;T;.
Sift4G	Pathogenic	0.0	.;.;.;D;D
Vest4		0.72
MutPred		0.79		Loss of MoRF binding (P = 0.0784);.;.;.;.;
MVP		0.71
MPC		0.20
ClinPred		0.62	D
GERP RS		5.3
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1085308017; hg19: chr18-21494503;