rs1258173126

Variant names:

• chr5-157460324-G-A
• rs1258173126
• NM_001099287.2:c.4G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-157460324-G-A
• chr5-157460324-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001099287.2(NIPAL4):​c.4G>A​(p.Glu2Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000716 in 1,395,684 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. E2D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: NIPAL4 NM_001099287.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.44
• Publications: 1 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]

ENSG00000285868 (HGNC:):

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2012029).

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.4G>A	p.Glu2Lys	missense	Exon 1 of 6	NP_001092757.2	Q0D2K0-1
	NIPAL4	NM_001172292.2		c.4G>A	p.Glu2Lys	missense	Exon 1 of 5	NP_001165763.2	Q0D2K0-2
	NIPAL4-DT	NR_136204.1		n.-224C>T		upstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NIPAL4	ENST00000311946.8	TSL:1 MANE Select	c.4G>A	p.Glu2Lys	missense	Exon 1 of 6	ENSP00000311687.8	Q0D2K0-1
	NIPAL4	ENST00000521390.5	TSL:1	n.109G>A		non_coding_transcript_exon	Exon 1 of 4
	NIPAL4	ENST00000435489.7	TSL:2	c.4G>A	p.Glu2Lys	missense	Exon 1 of 5	ENSP00000406456.3	Q0D2K0-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000704 AC: 1 AN: 142044 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.16e-7 AC: 1 AN: 1395684 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 688238

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31488

American (AMR) AF: 0.00 AC: 0 AN: 35716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25118

East Asian (EAS) AF: 0.00 AC: 0 AN: 35684

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79156

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47658

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4836

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078226

Other (OTH) AF: 0.00 AC: 0 AN: 57802

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.041	T
Eigen	Benign	0.064
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.67	T
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.20	T
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Benign	0.81	L
PhyloP100		4.4
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.43
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.024	D
Polyphen		0.88	P
Vest4		0.33
MutPred		0.36		Gain of ubiquitination at E64 (P = 0.0104)
MVP		0.59
MPC		0.42
ClinPred		0.90	D
GERP RS		3.6
PromoterAI		-0.048	Neutral
Varity_R		0.26
gMVP		0.21
Mutation Taster		=82/18	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: rs1258173126; hg19: chr5-156887332;