rs187947581

Variant names:

• chr1-5875004-T-A
• NM_015102.5:c.2914A>T

Your query was ambiguous. Multiple possible variants found:

• chr1-5875004-T-A
• chr1-5875004-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM5

The NM_015102.5(NPHP4):​c.2914A>T​(p.Ser972Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,824 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. S972G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: NPHP4 NM_015102.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.58

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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-5875004-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPHP4	NM_015102.5	c.2914A>T	p.Ser972Cys	missense_variant	Exon 21 of 30	ENST00000378156.9	NP_055917.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPHP4	ENST00000378156.9	c.2914A>T	p.Ser972Cys	missense_variant	Exon 21 of 30	1	NM_015102.5	ENSP00000367398.4
NPHP4	ENST00000378169.7	n.*1815A>T		non_coding_transcript_exon_variant	Exon 18 of 27	1		ENSP00000367411.3
NPHP4	ENST00000489180.6	n.*725A>T		non_coding_transcript_exon_variant	Exon 24 of 33	2		ENSP00000423747.1
NPHP4	ENST00000378169.7	n.*1815A>T		3_prime_UTR_variant	Exon 18 of 27	1		ENSP00000367411.3
NPHP4	ENST00000489180.6	n.*725A>T		3_prime_UTR_variant	Exon 24 of 33	2		ENSP00000423747.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459824 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726252

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: 8.99e-7

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	Benign	0.11
BayesDel_addAF	Uncertain	0.093	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.51	D
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.75	T
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.74	D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Uncertain	2.7	M
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.51
Sift	Benign	0.035	D
Sift4G	Uncertain	0.016	D
Polyphen		0.99	D
Vest4		0.55
MutPred		0.45		Gain of catalytic residue at L973 (P = 0.0115);
MVP		0.95
MPC		0.32
ClinPred		0.96	D
GERP RS		3.7
Varity_R		0.23
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-5935064;