5-157468728-C-G

Variant names:

• chr5-157468728-C-G
• rs199422217
• NM_001099287.2:c.341C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PM2 PM5 BP4_Strong

The NM_001099287.2(NIPAL4):​c.341C>G​(p.Ala114Gly) variant causes a missense 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A114D) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.00021 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NIPAL4 NM_001099287.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.03
• Publications: 24 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-157468728-C-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.007375926).

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.341C>G	p.Ala114Gly	missense	Exon 4 of 6	NP_001092757.2	Q0D2K0-1
	NIPAL4	NM_001172292.2		c.284C>G	p.Ala95Gly	missense	Exon 3 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.341C>G	p.Ala114Gly	missense	Exon 4 of 6	ENSP00000311687.8	Q0D2K0-1
	NIPAL4	ENST00000435489.7	TSL:2	c.284C>G	p.Ala95Gly	missense	Exon 3 of 5	ENSP00000406456.3	Q0D2K0-2
	NIPAL4	ENST00000519150.1	TSL:5	n.*40C>G		non_coding_transcript_exon	Exon 5 of 7	ENSP00000430810.1	H0YC31

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00211 AC: 517 AN: 245384 AF XY: 0.00123

Gnomad AFR exome AF: 0.0112

Gnomad AMR exome AF: 0.000117

Gnomad ASJ exome AF: 0.000700

Gnomad EAS exome AF: 0.000447

Gnomad FIN exome AF: 0.00279

Gnomad NFE exome AF: 0.00229

Gnomad OTH exome AF: 0.00339

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000212 AC: 309 AN: 1455972 Hom.: 0 Cov.: 29 AF XY: 0.000221 AC XY: 160 AN XY: 724660

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

African (AFR) AF: 0.0000599 AC: 2 AN: 33382

American (AMR) AF: 0.00 AC: 0 AN: 44656

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39648

South Asian (SAS) AF: 0.00 AC: 0 AN: 86036

European-Finnish (FIN) AF: 0.00476 AC: 249 AN: 52348

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5756

European-Non Finnish (NFE) AF: 0.0000253 AC: 28 AN: 1107956

Other (OTH) AF: 0.000466 AC: 28 AN: 60084

⚠️ 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.: 32

ExAC AF: 0.0147 AC: 1783

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.012	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.46	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.054
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.0074	T
MetaSVM	Benign	-0.37	T
MutationAssessor	Benign	0.55	N
PhyloP100		2.0
PrimateAI	Benign	0.42	T
PROVEAN	Benign	0.20	N
REVEL	Benign	0.24
Sift	Benign	0.70	T
Sift4G	Benign	0.34	T
Polyphen		0.0010	B
Vest4		0.33
MPC		0.28
ClinPred		0.011	T
GERP RS		3.9
Varity_R		0.17
gMVP		0.46
Mutation Taster		=50/50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs199422217; hg19: chr5-156895736;