rs1287637

Positions:

• chr1-5875102-T-A
• chr1-5875102-T-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PVS1_Moderate BA1

The NM_015102.5(NPHP4):​c.2818-2A>T variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.17 in 1,593,470 control chromosomes in the GnomAD database, including 23,961 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.15 (1977 hom., cov: 32)
  • Exomes 𝑓: 0.17 (21984 hom.)
• Consequence: NPHP4 NM_015102.5 splice_acceptor, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.33

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 Likely_benign. Variant got -6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.052791405 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.3, offset of 6, new splice context is: cctcttgtctgctggcgcAGcag. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.182 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPHP4	NM_015102.5	c.2818-2A>T		splice_acceptor_variant, intron_variant		ENST00000378156.9	NP_055917.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPHP4	ENST00000378156.9	c.2818-2A>T		splice_acceptor_variant, intron_variant		1	NM_015102.5	ENSP00000367398.4
NPHP4	ENST00000378169.7	n.*1719-2A>T		splice_acceptor_variant, intron_variant		1		ENSP00000367411.3
NPHP4	ENST00000489180.6	n.*629-2A>T		splice_acceptor_variant, intron_variant		2		ENSP00000423747.1

Frequencies

GnomAD3 genomes AF: 0.154 AC: 23475 AN: 152104 Hom.: 1975 Cov.: 32

Gnomad AFR AF: 0.109

Gnomad AMI AF: 0.171

Gnomad AMR AF: 0.187

Gnomad ASJ AF: 0.252

Gnomad EAS AF: 0.183

Gnomad SAS AF: 0.166

Gnomad FIN AF: 0.0768

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.177

Gnomad OTH AF: 0.177

GnomAD4 exome AF: 0.172 AC: 247392 AN: 1441248 Hom.: 21984 Cov.: 33 AF XY: 0.173 AC XY: 123646 AN XY: 716558

Gnomad4 AFR exome AF: 0.105

Gnomad4 AMR exome AF: 0.203

Gnomad4 ASJ exome AF: 0.250

Gnomad4 EAS exome AF: 0.170

Gnomad4 SAS exome AF: 0.173

Gnomad4 FIN exome AF: 0.0836

Gnomad4 NFE exome AF: 0.174

Gnomad4 OTH exome AF: 0.174

GnomAD4 genome AF: 0.154 AC: 23487 AN: 152222 Hom.: 1977 Cov.: 32 AF XY: 0.151 AC XY: 11254 AN XY: 74410

Gnomad4 AFR AF: 0.109

Gnomad4 AMR AF: 0.188

Gnomad4 ASJ AF: 0.252

Gnomad4 EAS AF: 0.182

Gnomad4 SAS AF: 0.165

Gnomad4 FIN AF: 0.0768

Gnomad4 NFE AF: 0.177

Gnomad4 OTH AF: 0.175

Alfa AF: 0.177 Hom.: 1475

Bravo AF: 0.163

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	24
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1287637; hg19: chr1-5935162;