5-157463166-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001099287.2(NIPAL4):c.110T>C(p.Val37Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00514 in 1,613,968 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V37M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0030 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0054 (24 hom.)
• Consequence: NIPAL4 NM_001099287.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0240

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0038264692).
• BP6: Variant 5-157463166-T-C is Benign according to our data. Variant chr5-157463166-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 352506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00301 (458/152276) while in subpopulation NFE AF= 0.00581 (395/68002). AF 95% confidence interval is 0.00534. There are 2 homozygotes in gnomad4. There are 186 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NIPAL4	NM_001099287.2	c.110T>C	p.Val37Ala	missense_variant	2/6	ENST00000311946.8
NIPAL4	NM_001172292.2	c.110T>C	p.Val37Ala	missense_variant	2/5
NIPAL4	XM_011534552.2	c.-200T>C		5_prime_UTR_variant	2/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NIPAL4	ENST00000311946.8	c.110T>C	p.Val37Ala	missense_variant	2/6	1	NM_001099287.2	P1

Frequencies

GnomAD3 genomes AF: 0.00302 AC: 459 AN: 152158 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000941

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00582

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00280 AC: 698 AN: 249266 Hom.: 3 AF XY: 0.00251 AC XY: 339 AN XY: 135226

Gnomad AFR exome AF: 0.000904

Gnomad AMR exome AF: 0.000550

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000980

Gnomad FIN exome AF: 0.000603

Gnomad NFE exome AF: 0.00544

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.00536 AC: 7841 AN: 1461692 Hom.: 24 Cov.: 31 AF XY: 0.00512 AC XY: 3725 AN XY: 727126

Gnomad4 AFR exome AF: 0.000986

Gnomad4 AMR exome AF: 0.000604

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000788

Gnomad4 FIN exome AF: 0.000674

Gnomad4 NFE exome AF: 0.00666

Gnomad4 OTH exome AF: 0.00452

GnomAD4 genome AF: 0.00301 AC: 458 AN: 152276 Hom.: 2 Cov.: 32 AF XY: 0.00250 AC XY: 186 AN XY: 74452

Gnomad4 AFR AF: 0.000938

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000831

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00581

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00464 Hom.: 1

Bravo AF: 0.00311

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.00124 AC: 5

ESP6500EA AF: 0.00622 AC: 52

ExAC AF: 0.00277 AC: 335

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00529

EpiControl AF: 0.00427

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

NIPAL4-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 18, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Autosomal recessive congenital ichthyosis 6 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jul 27, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	0.36
Dann	Benign	0.52
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.037	N
LIST_S2	Benign	0.27	T;T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.0038	T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	0.46	N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.18	N;N
REVEL	Benign	0.15
Sift	Benign	0.36	T;T
Sift4G	Benign	0.48	T;T
Polyphen		0.0	B;B
Vest4		0.13
MVP		0.17
MPC		0.33
ClinPred		0.014	T
GERP RS		-8.8
Varity_R		0.021
gMVP		0.23

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: rs183419459; hg19: chr5-156890174;