rs200128117

Variant names:

• chr1-5978373-C-G
• NM_015102.5:c.176G>C

Your query was ambiguous. Multiple possible variants found:

• chr1-5978373-C-G
• chr1-5978373-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_015102.5(NPHP4):​c.176G>C​(p.Arg59Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000687 in 1,455,406 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R59Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: NPHP4 NM_015102.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.48

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.868

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPHP4	NM_015102.5	c.176G>C	p.Arg59Pro	missense_variant	Exon 3 of 30	ENST00000378156.9	NP_055917.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPHP4	ENST00000378156.9	c.176G>C	p.Arg59Pro	missense_variant	Exon 3 of 30	1	NM_015102.5	ENSP00000367398.4
NPHP4	ENST00000378169.7	n.176G>C		non_coding_transcript_exon_variant	Exon 3 of 27	1		ENSP00000367411.3
NPHP4	ENST00000489180.6	n.176G>C		non_coding_transcript_exon_variant	Exon 3 of 33	2		ENSP00000423747.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455406 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 723476

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: 9.02e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D;.
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.87	D;D
MetaSVM	Uncertain	0.74	D
MutationAssessor	Uncertain	2.4	M;M
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-2.8	D;.
REVEL	Pathogenic	0.75
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.93
MutPred		0.56		Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);
MVP		0.97
MPC		0.46
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.85
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-6038433;