1-5865311-G-A

Variant names:

• chr1-5865311-G-A
• rs1287634
• ENST00000460696.1:n.1771C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000460696.1(NPHP4):​n.1771C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.402 in 1,482,882 control chromosomes in the GnomAD database, including 122,548 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (10196 hom., cov: 33)
  • Exomes 𝑓: 0.41 (112352 hom.)
• Consequence: NPHP4 ENST00000460696.1 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.09
• Publications: 10 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=-0.9).
• BP6: Variant 1-5865311-G-A is Benign according to our data. Variant chr1-5865311-G-A is described in ClinVar as [Benign]. Clinvar id is 260559.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.415 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPHP4	NM_015102.5	c.3645-38C>T		intron_variant	Intron 26 of 29	ENST00000378156.9	NP_055917.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPHP4	ENST00000378156.9	c.3645-38C>T		intron_variant	Intron 26 of 29	1	NM_015102.5	ENSP00000367398.4
NPHP4	ENST00000378169.7	n.*2546-38C>T		intron_variant	Intron 23 of 26	1		ENSP00000367411.3
NPHP4	ENST00000489180.6	n.*1456-38C>T		intron_variant	Intron 29 of 32	2		ENSP00000423747.1

Frequencies

GnomAD3 genomes AF: 0.353 AC: 53654 AN: 152066 Hom.: 10194 Cov.: 33

Gnomad AFR AF: 0.208

Gnomad AMI AF: 0.551

Gnomad AMR AF: 0.369

Gnomad ASJ AF: 0.460

Gnomad EAS AF: 0.268

Gnomad SAS AF: 0.430

Gnomad FIN AF: 0.427

Gnomad MID AF: 0.392

Gnomad NFE AF: 0.418

Gnomad OTH AF: 0.362

GnomAD2 exomes AF: 0.389 AC: 48526 AN: 124902 AF XY: 0.393

Gnomad AFR exome AF: 0.201

Gnomad AMR exome AF: 0.368

Gnomad ASJ exome AF: 0.474

Gnomad EAS exome AF: 0.252

Gnomad FIN exome AF: 0.439

Gnomad NFE exome AF: 0.427

Gnomad OTH exome AF: 0.410

GnomAD4 exome AF: 0.408 AC: 542555 AN: 1330696 Hom.: 112352 Cov.: 29 AF XY: 0.409 AC XY: 264386 AN XY: 647122

African (AFR) AF: 0.199 AC: 6162 AN: 30994

American (AMR) AF: 0.366 AC: 12400 AN: 33846

Ashkenazi Jewish (ASJ) AF: 0.461 AC: 10025 AN: 21768

East Asian (EAS) AF: 0.266 AC: 9382 AN: 35282

South Asian (SAS) AF: 0.432 AC: 30507 AN: 70694

European-Finnish (FIN) AF: 0.424 AC: 16910 AN: 39836

Middle Eastern (MID) AF: 0.406 AC: 1654 AN: 4074

European-Non Finnish (NFE) AF: 0.417 AC: 433336 AN: 1039052

Other (OTH) AF: 0.402 AC: 22179 AN: 55150

GnomAD4 genome AF: 0.353 AC: 53673 AN: 152186 Hom.: 10196 Cov.: 33 AF XY: 0.355 AC XY: 26412 AN XY: 74398

African (AFR) AF: 0.208 AC: 8630 AN: 41542

American (AMR) AF: 0.369 AC: 5651 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.460 AC: 1597 AN: 3470

East Asian (EAS) AF: 0.268 AC: 1383 AN: 5166

South Asian (SAS) AF: 0.430 AC: 2072 AN: 4818

European-Finnish (FIN) AF: 0.427 AC: 4529 AN: 10598

Middle Eastern (MID) AF: 0.395 AC: 116 AN: 294

European-Non Finnish (NFE) AF: 0.418 AC: 28435 AN: 67978

Other (OTH) AF: 0.359 AC: 759 AN: 2114

Alfa AF: 0.395 Hom.: 32735

Bravo AF: 0.339

Asia WGS AF: 0.376 AC: 1305 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

May 13, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nephronophthisis 4 Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.84
DANN	Benign	0.54
PhyloP100		-2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1287634; hg19: chr1-5925371; COSMIC: COSV65395132; COSMIC: COSV65395132;