chr1-5978292-G-T

Variant names:

• chr1-5978292-G-T
• rs201998215
• NM_015102.5:c.257C>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015102.5(NPHP4):​c.257C>A​(p.Pro86Gln) 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 benign outcome for this variant. 15/21 in silico tools predict a benign 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. P86L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 29)
• Consequence: NPHP4 NM_015102.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.850

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16857594).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPHP4	NM_015102.5	c.257C>A	p.Pro86Gln	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.257C>A	p.Pro86Gln	missense_variant	Exon 3 of 30	1	NM_015102.5	ENSP00000367398.4
NPHP4	ENST00000378169.7	n.257C>A		non_coding_transcript_exon_variant	Exon 3 of 27	1		ENSP00000367411.3
NPHP4	ENST00000489180.6	n.257C>A		non_coding_transcript_exon_variant	Exon 3 of 33	2		ENSP00000423747.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.065	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.13	T;.
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.72	T;T
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	0.81	L;L
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.5	N;.
REVEL	Benign	0.13
Sift	Uncertain	0.0060	D;.
Sift4G	Uncertain	0.0090	D;D
Polyphen		0.35	B;.
Vest4		0.36
MutPred		0.29		Loss of glycosylation at P86 (P = 0.0079);Loss of glycosylation at P86 (P = 0.0079);
MVP		0.86
MPC		0.10
ClinPred		0.12	T
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.040
gMVP		0.30

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

LitVar

Other links and lift over

dbSNP: rs201998215; hg19: chr1-6038352;