5-157471682-A-T

Variant summary

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

The NM_001099287.2(NIPAL4):c.451A>T(p.Arg151Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R151G) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NIPAL4 NM_001099287.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.01

Genes affected

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]

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NIPAL4	NM_001099287.2	c.451A>T	p.Arg151Trp	missense_variant	5/6	ENST00000311946.8
NIPAL4	NM_001172292.2	c.394A>T	p.Arg132Trp	missense_variant	4/5
NIPAL4	XM_011534552.2	c.142A>T	p.Arg48Trp	missense_variant	5/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NIPAL4	ENST00000311946.8	c.451A>T	p.Arg151Trp	missense_variant	5/6	1	NM_001099287.2	P1
NIPAL4	ENST00000435489.7	c.394A>T	p.Arg132Trp	missense_variant	4/5	2
ADAM19	ENST00000517951.5	c.*1741+16583T>A		intron_variant, NMD_transcript_variant		2
NIPAL4	ENST00000519150.1	c.*150A>T		3_prime_UTR_variant, NMD_transcript_variant	6/7	5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1455014 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 722996

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.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.060	T
BayesDel_noAF	Benign	-0.32
Cadd	Uncertain	23
Dann	Uncertain	1.0
Eigen	Benign	0.053
Eigen_PC	Benign	0.072
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Pathogenic	0.97	D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.54	D;D
MetaSVM	Uncertain	-0.18	T
MutationTaster	Benign	3.9e-20	P;P;P
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.6	D;D
REVEL	Uncertain	0.33
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.0090	D;D
Polyphen		0.93	P;P
Vest4		0.28
MutPred		0.53		.;Gain of catalytic residue at E214 (P = 0.1137);
MVP		0.43
MPC		0.69
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.40
gMVP		0.56

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: rs6860507; hg19: chr5-156898690;