5-157460331-G-C

Position:

• chr5-157460331-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_001099287.2(NIPAL4):​c.11G>C​(p.Arg4Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000215 in 1,395,418 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: NIPAL4 NM_001099287.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.691

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07876223).
• BP6: Variant 5-157460331-G-C is Benign according to our data. Variant chr5-157460331-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 2624350.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NIPAL4	NM_001099287.2	c.11G>C	p.Arg4Pro	missense_variant	1/6	ENST00000311946.8	NP_001092757.2
NIPAL4	NM_001172292.2	c.11G>C	p.Arg4Pro	missense_variant	1/5		NP_001165763.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NIPAL4	ENST00000311946.8	c.11G>C	p.Arg4Pro	missense_variant	1/6	1	NM_001099287.2	ENSP00000311687.8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000211 AC: 3 AN: 141990 Hom.: 0 AF XY: 0.0000130 AC XY: 1 AN XY: 76838

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000190

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000240

GnomAD4 exome AF: 0.00000215 AC: 3 AN: 1395418 Hom.: 0 Cov.: 32 AF XY: 0.00000145 AC XY: 1 AN XY: 688090

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000561

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000173

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 14, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	20
DANN	Benign	0.90
DEOGEN2	Benign	0.032	.;T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.53	T;T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.079	T;T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	-0.14	N;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.89	N;N
REVEL	Benign	0.25
Sift	Benign	0.17	T;T
Sift4G	Benign	0.12	T;T
Polyphen		0.0	B;B
Vest4		0.099
MutPred		0.35		Gain of glycosylation at S68 (P = 0.0351);Gain of glycosylation at S68 (P = 0.0351);
MVP		0.32
MPC		0.39
ClinPred		0.14	T
GERP RS		-0.60
Varity_R		0.26
gMVP		0.28

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: rs1346137579; hg19: chr5-156887339;