1-5904788-G-C

Variant names:

• chr1-5904788-G-C
• NM_015102.5:c.1972C>G

Variant summary

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

The NM_015102.5(NPHP4):​c.1972C>G​(p.Arg658Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,682 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R658Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NPHP4 NM_015102.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0520

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=0.0720295).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPHP4	NM_015102.5	c.1972C>G	p.Arg658Gly	missense_variant	Exon 16 of 30	ENST00000378156.9	NP_055917.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPHP4	ENST00000378156.9	c.1972C>G	p.Arg658Gly	missense_variant	Exon 16 of 30	1	NM_015102.5	ENSP00000367398.4
NPHP4	ENST00000378169.7	n.*873C>G		non_coding_transcript_exon_variant	Exon 13 of 27	1		ENSP00000367411.3
NPHP4	ENST00000489180.6	n.1969C>G		non_coding_transcript_exon_variant	Exon 16 of 33	2		ENSP00000423747.1
NPHP4	ENST00000378169.7	n.*873C>G		3_prime_UTR_variant	Exon 13 of 27	1		ENSP00000367411.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461682 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727122

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.026	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	14
DANN	Benign	0.91
DEOGEN2	Benign	0.089	T;.
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.63	T;T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.072	T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.4	L;.
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.18	N;.
REVEL	Uncertain	0.29
Sift	Benign	0.46	T;.
Sift4G	Benign	0.35	T;T
Polyphen		0.0030	B;.
Vest4		0.13
MutPred		0.33		Loss of solvent accessibility (P = 0.0044);.;
MVP		0.78
MPC		0.081
ClinPred		0.073	T
GERP RS		2.0
Varity_R		0.072
gMVP		0.17

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-5964848;