chr1-5873220-C-T

Variant names:

• chr1-5873220-C-T
• rs115555125
• NM_015102.5:c.3315+32G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015102.5(NPHP4):​c.3315+32G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00128 in 1,570,316 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0058 (11 hom., cov: 33)
  • Exomes 𝑓: 0.00080 (7 hom.)
• Consequence: NPHP4 NM_015102.5 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.442
• Publications: 1 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 1-5873220-C-T is Benign according to our data. Variant chr1-5873220-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 260555.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00576 (877/152326) while in subpopulation AFR AF = 0.0187 (777/41572). AF 95% confidence interval is 0.0176. There are 11 homozygotes in GnomAd4. There are 418 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPHP4	NM_015102.5	c.3315+32G>A		intron_variant	Intron 23 of 29	ENST00000378156.9	NP_055917.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPHP4	ENST00000378156.9	c.3315+32G>A		intron_variant	Intron 23 of 29	1	NM_015102.5	ENSP00000367398.4
NPHP4	ENST00000378169.7	n.*2216+32G>A		intron_variant	Intron 20 of 26	1		ENSP00000367411.3
NPHP4	ENST00000489180.6	n.*1126+32G>A		intron_variant	Intron 26 of 32	2		ENSP00000423747.1

Frequencies

GnomAD3 genomes AF: 0.00576 AC: 876 AN: 152208 Hom.: 11 Cov.: 33

Gnomad AFR AF: 0.0187

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.00518

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00670

GnomAD2 exomes AF: 0.00164 AC: 407 AN: 248122 AF XY: 0.00146

Gnomad AFR exome AF: 0.0187

Gnomad AMR exome AF: 0.00102

Gnomad ASJ exome AF: 0.00329

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000140

Gnomad NFE exome AF: 0.000169

Gnomad OTH exome AF: 0.00149

GnomAD4 exome AF: 0.000804 AC: 1140 AN: 1417990 Hom.: 7 Cov.: 25 AF XY: 0.000811 AC XY: 574 AN XY: 707908

African (AFR) AF: 0.0204 AC: 666 AN: 32592

American (AMR) AF: 0.00110 AC: 49 AN: 44604

Ashkenazi Jewish (ASJ) AF: 0.00294 AC: 76 AN: 25846

East Asian (EAS) AF: 0.00 AC: 0 AN: 39464

South Asian (SAS) AF: 0.000528 AC: 45 AN: 85298

European-Finnish (FIN) AF: 0.000112 AC: 6 AN: 53352

Middle Eastern (MID) AF: 0.00386 AC: 22 AN: 5700

European-Non Finnish (NFE) AF: 0.000150 AC: 161 AN: 1072222

Other (OTH) AF: 0.00195 AC: 115 AN: 58912

GnomAD4 genome AF: 0.00576 AC: 877 AN: 152326 Hom.: 11 Cov.: 33 AF XY: 0.00561 AC XY: 418 AN XY: 74480

African (AFR) AF: 0.0187 AC: 777 AN: 41572

American (AMR) AF: 0.00327 AC: 50 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00518 AC: 18 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4832

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10626

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68014

Other (OTH) AF: 0.00664 AC: 14 AN: 2110

Alfa AF: 0.00363 Hom.: 3

Bravo AF: 0.00702

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.010
DANN	Benign	0.65
PhyloP100		-0.44
Mutation Taster		=100/0	polymorphism

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: rs115555125; hg19: chr1-5933280;