rs555164

Positions:

• chr1-5866447-T-A
• chr1-5866447-T-C
• chr1-5866447-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_015102.5(NPHP4):​c.3570A>T​(p.Glu1190Asp) 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 pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. E1190E) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NPHP4 NM_015102.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.305

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.774

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPHP4	NM_015102.5	c.3570A>T	p.Glu1190Asp	missense_variant	26/30	ENST00000378156.9	NP_055917.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPHP4	ENST00000378156.9	c.3570A>T	p.Glu1190Asp	missense_variant	26/30	1	NM_015102.5	ENSP00000367398	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1442416 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 716294

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.052	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.080
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.083	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Uncertain	0.12	D
MutationAssessor	Uncertain	2.2	M
MutationTaster	Benign	0.0039	P
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.36
Sift	Uncertain	0.023	D
Sift4G	Uncertain	0.013	D
Polyphen		1.0	D
Vest4		0.39
MutPred		0.40		Gain of catalytic residue at G1189 (P = 0.1069);
MVP		0.81
MPC		0.37
ClinPred		0.95	D
GERP RS		3.2
Varity_R		0.21
gMVP		0.44

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: rs555164; hg19: chr1-5926507;