ENST00000517951.5:n.*1741+28129A>G

Variant names:

• chr5-157460136-T-C
• rs1581262988
• ENST00000517951.5:n.*1741+28129A>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The ENST00000517951.5(ADAM19):​n.*1741+28129A>G variant causes a intron 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. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ADAM19 ENST00000517951.5 intron
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.193

Genes affected

ADAM19 (HGNC:197): (ADAM metallopeptidase domain 19) This gene encodes a member of the ADAM (a disintegrin and metalloprotease domain) family. Members of this family are membrane-anchored proteins structurally related to snake venom disintegrins and have been implicated in a variety of biological processes involving cell-cell and cell-matrix interactions, including fertilization, muscle development, and neurogenesis. This member is a type I transmembrane protein and serves as a marker for dendritic cell differentiation. It has been demonstrated to be an active metalloproteinase, which may be involved in normal physiological processes such as cell migration, cell adhesion, cell-cell and cell-matrix interactions, and signal transduction. It is proposed to play a role in pathological processes, such as cancer, inflammatory diseases, renal diseases, and Alzheimer's disease. [provided by RefSeq, May 2013]

NIPAL4 (HGNC:28018): (NIPA like domain containing 4) This gene likely encodes a membrane receptor. Mutations in this gene have been associated with autosomal recessive congenital ichthyosis. [provided by RefSeq, Feb 2010]

ENSG00000285868 (HGNC:):

NIPAL4-DT (HGNC:55542): (NIPAL4 divergent transcript)

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-157460136-T-C is Pathogenic according to our data. Variant chr5-157460136-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 638533.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.38872242). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NIPAL4	NM_001099287.2	c.-185T>C		upstream_gene_variant		ENST00000311946.8	NP_001092757.2
NIPAL4	NM_001172292.2	c.-185T>C		upstream_gene_variant			NP_001165763.2
NIPAL4-DT	NR_136204.1	n.-36A>G		upstream_gene_variant
NIPAL4-DT	NR_136205.1	n.-36A>G		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NIPAL4	ENST00000311946.8	c.-185T>C		upstream_gene_variant		1	NM_001099287.2	ENSP00000311687.8
ENSG00000285868	ENST00000519499.2	c.-2361A>G		upstream_gene_variant		3		ENSP00000496943.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Autosomal recessive congenital ichthyosis 6 Pathogenic:1

May 16, 2019

Institute for Human Genetics, University Medical Center Freiburg

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Benign	-0.39
CADD	Benign	9.4
DANN	Benign	0.57
DEOGEN2	Benign	0.030	.;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0025	N
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.39	T;T
MetaSVM	Benign	-0.49	T
PROVEAN	Benign	0.10	N;N
REVEL	Benign	0.18
Sift	Pathogenic	0.0	D;D
Polyphen		0.0	B;B
Vest4		0.12
MutPred		0.79		Gain of phosphorylation at M1 (P = 0.0028);Gain of phosphorylation at M1 (P = 0.0028);
MVP		0.18
ClinPred		0.15	T
GERP RS		0.70
Varity_R		0.53
gMVP		0.18

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: rs1581262988; hg19: chr5-156887144;