chr1-5863279-C-A

Variant names:

• chr1-5863279-C-A
• rs1045851958
• NM_015102.5:c.4267G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_015102.5(NPHP4):​c.4267G>T​(p.Val1423Phe) variant causes a missense change involving the alteration of a 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. V1423I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NPHP4 NM_015102.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.45
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• nephronophthisis 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), G2P
• Senior-Loken syndrome 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• nephronophthisis 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Senior-Loken syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.82

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPHP4	NM_015102.5	c.4267G>T	p.Val1423Phe	missense_variant	Exon 30 of 30	ENST00000378156.9	NP_055917.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPHP4	ENST00000378156.9	c.4267G>T	p.Val1423Phe	missense_variant	Exon 30 of 30	1	NM_015102.5	ENSP00000367398.4
NPHP4	ENST00000378169.7	n.*3168G>T		non_coding_transcript_exon_variant	Exon 27 of 27	1		ENSP00000367411.3
NPHP4	ENST00000489180.6	n.*2078G>T		non_coding_transcript_exon_variant	Exon 33 of 33	2		ENSP00000423747.1
NPHP4	ENST00000378169.7	n.*3168G>T		3_prime_UTR_variant	Exon 27 of 27	1		ENSP00000367411.3
NPHP4	ENST00000489180.6	n.*2078G>T		3_prime_UTR_variant	Exon 33 of 33	2		ENSP00000423747.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.80	T
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		7.5
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.87
MutPred		0.28		Gain of ubiquitination at K1422 (P = 0.0985);
MVP		0.99
MPC		0.43
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.54
gMVP		0.89
Mutation Taster		=23/77	disease causing

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

Other links and lift over

dbSNP: rs1045851958; hg19: chr1-5923339;