rs878854994

Positions:

• chr1-5961868-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000378156.9(NPHP4):​c.599A>G​(p.His200Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,484 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. H200H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NPHP4 ENST00000378156.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.29

Genes affected

NPHP4 (HGNC:19104): (nephrocystin 4) This gene encodes a protein involved in renal tubular development and function. This protein interacts with nephrocystin, and belongs to a multifunctional complex that is localized to actin- and microtubule-based structures. Mutations in this gene are associated with nephronophthisis type 4, a renal disease, and with Senior-Loken syndrome type 4, a combination of nephronophthisis and retinitis pigmentosa. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPHP4	NM_015102.5	c.599A>G	p.His200Arg	missense_variant	6/30	ENST00000378156.9	NP_055917.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPHP4	ENST00000378156.9	c.599A>G	p.His200Arg	missense_variant	6/30	1	NM_015102.5	ENSP00000367398	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461484 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727016

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Nephronophthisis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 05, 2022

This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 200 of the NPHP4 protein (p.His200Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NPHP4-related conditions. ClinVar contains an entry for this variant (Variation ID: 240971). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.85	T;T
M_CAP	Benign	0.082	D
MetaRNN	Uncertain	0.47	T;T
MetaSVM	Uncertain	0.54	D
MutationAssessor	Uncertain	2.4	M;M
MutationTaster	Benign	0.99	D
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-4.4	D;.
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.46
MutPred		0.55		Gain of solvent accessibility (P = 0.0171);Gain of solvent accessibility (P = 0.0171);
MVP		0.95
MPC		0.20
ClinPred		0.99	D
GERP RS		4.3
Varity_R		0.68
gMVP		0.68

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: rs878854994; hg19: chr1-6021928;