1-5874621-C-G

Position:

• chr1-5874621-C-G

Variant summary

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

The NM_015102.5(NPHP4):​c.3081G>C​(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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. 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: Not reported in ClinVar
• 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>C	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>C	p.Lys1027Asn	missense_variant	22/30	1	NM_015102.5	ENSP00000367398.4
NPHP4	ENST00000378169.7	n.*1982G>C		non_coding_transcript_exon_variant	19/27	1		ENSP00000367411.3
NPHP4	ENST00000489180.6	n.*892G>C		non_coding_transcript_exon_variant	25/33	2		ENSP00000423747.1
NPHP4	ENST00000378169.7	n.*1982G>C		3_prime_UTR_variant	19/27	1		ENSP00000367411.3
NPHP4	ENST00000489180.6	n.*892G>C		3_prime_UTR_variant	25/33	2		ENSP00000423747.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

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	0.56	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;