rs12120967

Positions:

• chr1-5905321-C-G
• chr1-5905321-C-T

Variant summary

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

The ENST00000378156.9(NPHP4):​c.1926G>C​(p.Glu642Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. E642K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NPHP4 ENST00000378156.9 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.740

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	Protein	UniProt
NPHP4	NM_015102.5	c.1926G>C	p.Glu642Asp	missense_variant	15/30	ENST00000378156.9	NP_055917.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPHP4	ENST00000378156.9	c.1926G>C	p.Glu642Asp	missense_variant	15/30	1	NM_015102.5	ENSP00000367398	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Benign	0.0018	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	13
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T;.
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.85	D;T
M_CAP	Benign	0.049	D
MetaRNN	Uncertain	0.54	D;D
MetaSVM	Uncertain	0.50	D
MutationAssessor	Uncertain	2.7	M;.
MutationTaster	Benign	1.0	P
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.7	N;.
REVEL	Uncertain	0.37
Sift	Benign	0.069	T;.
Sift4G	Uncertain	0.044	D;T
Polyphen		1.0	D;.
Vest4		0.41
MutPred		0.67		Loss of helix (P = 0.0444);.;
MVP		0.90
MPC		0.38
ClinPred		0.87	D
GERP RS		-4.3
Varity_R		0.094
gMVP		0.48

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

LitVar

Other links and lift over

dbSNP: rs12120967; hg19: chr1-5965381;