NM_015102.5:c.2485+38C>T

Variant names:

• chr1-5887248-G-A
• rs41280814
• NM_015102.5:c.2485+38C>T

Variant summary

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

The NM_015102.5(NPHP4):​c.2485+38C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.153 in 1,572,348 control chromosomes in the GnomAD database, including 19,477 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1362 hom., cov: 33)
  • Exomes 𝑓: 0.16 (18115 hom.)
• Consequence: NPHP4 NM_015102.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.10
• Publications: 2 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=-0.85).
• BP6: Variant 1-5887248-G-A is Benign according to our data. Variant chr1-5887248-G-A is described in ClinVar as Benign. ClinVar VariationId is 260546.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.163 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPHP4	NM_015102.5	c.2485+38C>T		intron_variant	Intron 18 of 29	ENST00000378156.9	NP_055917.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPHP4	ENST00000378156.9	c.2485+38C>T		intron_variant	Intron 18 of 29	1	NM_015102.5	ENSP00000367398.4
NPHP4	ENST00000378169.7	n.*1386+38C>T		intron_variant	Intron 15 of 26	1		ENSP00000367411.3
NPHP4	ENST00000489180.6	n.2482+38C>T		intron_variant	Intron 18 of 32	2		ENSP00000423747.1

Frequencies

GnomAD3 genomes AF: 0.118 AC: 17988 AN: 152154 Hom.: 1363 Cov.: 33

Gnomad AFR AF: 0.0333

Gnomad AMI AF: 0.161

Gnomad AMR AF: 0.113

Gnomad ASJ AF: 0.232

Gnomad EAS AF: 0.0756

Gnomad SAS AF: 0.120

Gnomad FIN AF: 0.131

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.165

Gnomad OTH AF: 0.136

GnomAD2 exomes AF: 0.134 AC: 26627 AN: 198424 AF XY: 0.138

Gnomad AFR exome AF: 0.0275

Gnomad AMR exome AF: 0.0789

Gnomad ASJ exome AF: 0.230

Gnomad EAS exome AF: 0.0795

Gnomad FIN exome AF: 0.140

Gnomad NFE exome AF: 0.172

Gnomad OTH exome AF: 0.151

GnomAD4 exome AF: 0.156 AC: 221859 AN: 1420076 Hom.: 18115 Cov.: 30 AF XY: 0.156 AC XY: 109355 AN XY: 702458

African (AFR) AF: 0.0269 AC: 879 AN: 32632

American (AMR) AF: 0.0833 AC: 3377 AN: 40524

Ashkenazi Jewish (ASJ) AF: 0.223 AC: 5585 AN: 25012

East Asian (EAS) AF: 0.0788 AC: 2992 AN: 37970

South Asian (SAS) AF: 0.117 AC: 9584 AN: 81910

European-Finnish (FIN) AF: 0.143 AC: 7167 AN: 50130

Middle Eastern (MID) AF: 0.137 AC: 779 AN: 5676

European-Non Finnish (NFE) AF: 0.168 AC: 182402 AN: 1087484

Other (OTH) AF: 0.155 AC: 9094 AN: 58738

GnomAD4 genome AF: 0.118 AC: 17983 AN: 152272 Hom.: 1362 Cov.: 33 AF XY: 0.117 AC XY: 8728 AN XY: 74454

African (AFR) AF: 0.0333 AC: 1383 AN: 41574

American (AMR) AF: 0.113 AC: 1722 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.232 AC: 804 AN: 3470

East Asian (EAS) AF: 0.0754 AC: 390 AN: 5172

South Asian (SAS) AF: 0.120 AC: 578 AN: 4832

European-Finnish (FIN) AF: 0.131 AC: 1394 AN: 10618

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.165 AC: 11239 AN: 68002

Other (OTH) AF: 0.135 AC: 285 AN: 2110

Alfa AF: 0.151 Hom.: 661

Bravo AF: 0.113

Asia WGS AF: 0.102 AC: 353 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	-0.85
CADD	Benign	0.036
DANN	Benign	0.64
PhyloP100		-2.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs41280814; hg19: chr1-5947308; COSMIC: COSV65397198; COSMIC: COSV65397198;