rs34248917

Positions:

• chr1-5890953-C-A
• chr1-5890953-C-T

Variant summary

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

The NM_015102.5(NPHP4):​c.2219G>T​(p.Arg740Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,450,580 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 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. R740H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NPHP4 NM_015102.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.523

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPHP4	NM_015102.5	c.2219G>T	p.Arg740Leu	missense_variant	17/30	ENST00000378156.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPHP4	ENST00000378156.9	c.2219G>T	p.Arg740Leu	missense_variant	17/30	1	NM_015102.5	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000417 AC: 1 AN: 239630 Hom.: 0 AF XY: 0.00000766 AC XY: 1 AN XY: 130472

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000340

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1450580 Hom.: 0 Cov.: 31 AF XY: 0.00000278 AC XY: 2 AN XY: 719680

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: 0.0000235

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000827 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.037	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	0.30
DANN	Benign	0.97
DEOGEN2	Benign	0.39	T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.81	T;T
M_CAP	Benign	0.084	D
MetaRNN	Uncertain	0.62	D;D
MetaSVM	Benign	-0.30	T
MutationAssessor	Uncertain	2.3	M;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.21	T
PROVEAN	Uncertain	-4.1	D;.
REVEL	Uncertain	0.37
Sift	Uncertain	0.026	D;.
Sift4G	Uncertain	0.013	D;D
Polyphen		0.85	P;.
Vest4		0.62
MutPred		0.32		Gain of methylation at R736 (P = 0.1109);.;
MVP		0.82
MPC		0.37
ClinPred		0.89	D
GERP RS		-7.2
Varity_R		0.11
gMVP		0.45

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: rs34248917; hg19: chr1-5951013;