chr1-5863996-C-A

Variant names:

• chr1-5863996-C-A
• NM_015102.5:c.4034G>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_015102.5(NPHP4):​c.4034G>T​(p.Gly1345Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,496 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. G1345D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NPHP4 NM_015102.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.45

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.857

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPHP4	NM_015102.5	c.4034G>T	p.Gly1345Val	missense_variant	Exon 29 of 30	ENST00000378156.9	NP_055917.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPHP4	ENST00000378156.9	c.4034G>T	p.Gly1345Val	missense_variant	Exon 29 of 30	1	NM_015102.5	ENSP00000367398.4
NPHP4	ENST00000378169.7	n.*2935G>T		non_coding_transcript_exon_variant	Exon 26 of 27	1		ENSP00000367411.3
NPHP4	ENST00000489180.6	n.*1845G>T		non_coding_transcript_exon_variant	Exon 32 of 33	2		ENSP00000423747.1
NPHP4	ENST00000378169.7	n.*2935G>T		3_prime_UTR_variant	Exon 26 of 27	1		ENSP00000367411.3
NPHP4	ENST00000489180.6	n.*1845G>T		3_prime_UTR_variant	Exon 32 of 33	2		ENSP00000423747.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461496 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727018

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Uncertain	0.57	D
MutationAssessor	Uncertain	2.6	M
PrimateAI	Benign	0.37	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Uncertain	0.62
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.76
MutPred		0.40		Loss of disorder (P = 0.0262);
MVP		0.93
MPC		0.43
ClinPred		1.0	D
GERP RS		4.2
Varity_R		0.43
gMVP		0.72

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-5924056;