5-157471682-A-T

Variant names:

• chr5-157471682-A-T
• rs6860507
• NM_001099287.2:c.451A>T

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 30 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001099287.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NIPAL4	NM_001099287.2	MANE Select	c.451A>T	p.Arg151Trp	missense	Exon 5 of 6	NP_001092757.2	Q0D2K0-1
	NIPAL4	NM_001172292.2		c.394A>T	p.Arg132Trp	missense	Exon 4 of 5	NP_001165763.2	Q0D2K0-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NIPAL4	ENST00000311946.8	TSL:1 MANE Select	c.451A>T	p.Arg151Trp	missense	Exon 5 of 6	ENSP00000311687.8	Q0D2K0-1
	NIPAL4	ENST00000435489.7	TSL:2	c.394A>T	p.Arg132Trp	missense	Exon 4 of 5	ENSP00000406456.3	Q0D2K0-2
	NIPAL4	ENST00000519150.1	TSL:5	n.*150A>T		non_coding_transcript_exon	Exon 6 of 7	ENSP00000430810.1	H0YC31

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

African (AFR) AF: 0.00 AC: 0 AN: 33400

American (AMR) AF: 0.00 AC: 0 AN: 43790

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25976

East Asian (EAS) AF: 0.00 AC: 0 AN: 39590

South Asian (SAS) AF: 0.00 AC: 0 AN: 84782

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53040

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5636

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108652

Other (OTH) AF: 0.00 AC: 0 AN: 60148

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Pathogenic	0.85	D
Eigen	Benign	0.053
Eigen_PC	Benign	0.072
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.54	D
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Benign	1.6	L
PhyloP100		2.0
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.33
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.93	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
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

dbSNP: rs6860507; hg19: chr5-156898690;