rs745993624

Positions:

• chr1-5874621-C-A
• chr1-5874621-C-G
• chr1-5874621-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_015102.5(NPHP4):​c.3081G>T​(p.Lys1027Asn) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. K1027K) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NPHP4 NM_015102.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.559

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]

NPHP4 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.773

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPHP4	NM_015102.5	c.3081G>T	p.Lys1027Asn	missense_variant	22/30	ENST00000378156.9	NP_055917.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPHP4	ENST00000378156.9	c.3081G>T	p.Lys1027Asn	missense_variant	22/30	1	NM_015102.5	ENSP00000367398.4
NPHP4	ENST00000378169.7	n.*1982G>T		non_coding_transcript_exon_variant	19/27	1		ENSP00000367411.3
NPHP4	ENST00000489180.6	n.*892G>T		non_coding_transcript_exon_variant	25/33	2		ENSP00000423747.1
NPHP4	ENST00000378169.7	n.*1982G>T		3_prime_UTR_variant	19/27	1		ENSP00000367411.3
NPHP4	ENST00000489180.6	n.*892G>T		3_prime_UTR_variant	25/33	2		ENSP00000423747.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Mar 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Benign	-0.014	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.56	D
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.083	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Uncertain	-0.026	T
MutationAssessor	Uncertain	2.5	M
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.050	T
Polyphen		1.0	D
Vest4		0.65
MutPred		0.37		Loss of methylation at K1027 (P = 0.012);
MVP		0.69
MPC		0.25
ClinPred		1.0	D
GERP RS		-6.3
Varity_R		0.59
gMVP		0.88

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: rs745993624; hg19: chr1-5934681;