chr1-5875102-T-A

Variant names:

• chr1-5875102-T-A
• rs1287637
• NM_015102.5:c.2818-2A>T

Variant summary

Our verdict is Likely benign. The variant received -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
• Publications: 34 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: Likely_benign. The variant received -6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.053024992 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 rank	MANE	Protein	UniProt
NPHP4	NM_015102.5	c.2818-2A>T		splice_acceptor_variant, intron_variant	Intron 20 of 29	ENST00000378156.9	NP_055917.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPHP4	ENST00000378156.9	c.2818-2A>T		splice_acceptor_variant, intron_variant	Intron 20 of 29	1	NM_015102.5	ENSP00000367398.4
NPHP4	ENST00000378169.7	n.*1719-2A>T		splice_acceptor_variant, intron_variant	Intron 17 of 26	1		ENSP00000367411.3
NPHP4	ENST00000489180.6	n.*629-2A>T		splice_acceptor_variant, intron_variant	Intron 23 of 32	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

African (AFR) AF: 0.105 AC: 3480 AN: 33252

American (AMR) AF: 0.203 AC: 8779 AN: 43150

Ashkenazi Jewish (ASJ) AF: 0.250 AC: 6485 AN: 25920

East Asian (EAS) AF: 0.170 AC: 6661 AN: 39224

South Asian (SAS) AF: 0.173 AC: 14649 AN: 84752

European-Finnish (FIN) AF: 0.0836 AC: 3675 AN: 43980

Middle Eastern (MID) AF: 0.230 AC: 1298 AN: 5652

European-Non Finnish (NFE) AF: 0.174 AC: 191967 AN: 1105398

Other (OTH) AF: 0.174 AC: 10398 AN: 59920

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

African (AFR) AF: 0.109 AC: 4535 AN: 41566

American (AMR) AF: 0.188 AC: 2871 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.252 AC: 875 AN: 3470

East Asian (EAS) AF: 0.182 AC: 940 AN: 5152

South Asian (SAS) AF: 0.165 AC: 798 AN: 4822

European-Finnish (FIN) AF: 0.0768 AC: 815 AN: 10608

Middle Eastern (MID) AF: 0.235 AC: 69 AN: 294

European-Non Finnish (NFE) AF: 0.177 AC: 12058 AN: 67992

Other (OTH) AF: 0.175 AC: 370 AN: 2112

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
PhyloP100		5.3
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

Other links and lift over

dbSNP: rs1287637; hg19: chr1-5935162;