rs868163

Variant names:

• chr1-5874430-A-G
• rs868163
• NM_015102.5:c.3231+41T>C

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.3231+41T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.634 in 1,468,040 control chromosomes in the GnomAD database, including 299,087 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.64 (31664 hom., cov: 31)
  • Exomes 𝑓: 0.63 (267423 hom.)
• Consequence: NPHP4 NM_015102.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -4.93
• Publications: 12 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=-0.92).
• BP6: Variant 1-5874430-A-G is Benign according to our data. Variant chr1-5874430-A-G is described in ClinVar as Benign. ClinVar VariationId is 260554.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.699 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015102.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHP4	NM_015102.5	MANE Select	c.3231+41T>C		intron	N/A	NP_055917.1
	NPHP4	NM_001291594.2		c.1695+41T>C		intron	N/A	NP_001278523.1
	NPHP4	NM_001291593.2		c.1692+41T>C		intron	N/A	NP_001278522.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHP4	ENST00000378156.9	TSL:1 MANE Select	c.3231+41T>C		intron	N/A	ENSP00000367398.4
	NPHP4	ENST00000378169.7	TSL:1	n.*2132+41T>C		intron	N/A	ENSP00000367411.3
	NPHP4	ENST00000489180.6	TSL:2	n.*1042+41T>C		intron	N/A	ENSP00000423747.1

Frequencies

GnomAD3 genomes AF: 0.640 AC: 96960 AN: 151466 Hom.: 31634 Cov.: 31

Gnomad AFR AF: 0.706

Gnomad AMI AF: 0.743

Gnomad AMR AF: 0.562

Gnomad ASJ AF: 0.642

Gnomad EAS AF: 0.289

Gnomad SAS AF: 0.614

Gnomad FIN AF: 0.644

Gnomad MID AF: 0.669

Gnomad NFE AF: 0.645

Gnomad OTH AF: 0.623

GnomAD2 exomes AF: 0.588 AC: 61027 AN: 103766 AF XY: 0.587

Gnomad AFR exome AF: 0.713

Gnomad AMR exome AF: 0.499

Gnomad ASJ exome AF: 0.648

Gnomad EAS exome AF: 0.269

Gnomad FIN exome AF: 0.638

Gnomad NFE exome AF: 0.644

Gnomad OTH exome AF: 0.610

GnomAD4 exome AF: 0.634 AC: 834220 AN: 1316454 Hom.: 267423 Cov.: 25 AF XY: 0.633 AC XY: 405729 AN XY: 641076

African (AFR) AF: 0.717 AC: 20805 AN: 29012

American (AMR) AF: 0.507 AC: 12920 AN: 25506

Ashkenazi Jewish (ASJ) AF: 0.646 AC: 13428 AN: 20792

East Asian (EAS) AF: 0.290 AC: 10123 AN: 34862

South Asian (SAS) AF: 0.624 AC: 42392 AN: 67974

European-Finnish (FIN) AF: 0.645 AC: 29340 AN: 45484

Middle Eastern (MID) AF: 0.647 AC: 3457 AN: 5342

European-Non Finnish (NFE) AF: 0.647 AC: 667956 AN: 1033130

Other (OTH) AF: 0.622 AC: 33799 AN: 54352

GnomAD4 genome AF: 0.640 AC: 97041 AN: 151586 Hom.: 31664 Cov.: 31 AF XY: 0.636 AC XY: 47073 AN XY: 74050

African (AFR) AF: 0.706 AC: 29165 AN: 41328

American (AMR) AF: 0.562 AC: 8569 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.642 AC: 2227 AN: 3468

East Asian (EAS) AF: 0.288 AC: 1485 AN: 5156

South Asian (SAS) AF: 0.613 AC: 2947 AN: 4804

European-Finnish (FIN) AF: 0.644 AC: 6763 AN: 10508

Middle Eastern (MID) AF: 0.668 AC: 195 AN: 292

European-Non Finnish (NFE) AF: 0.645 AC: 43712 AN: 67776

Other (OTH) AF: 0.624 AC: 1306 AN: 2092

Alfa AF: 0.636 Hom.: 46004

Bravo AF: 0.634

Asia WGS AF: 0.514 AC: 1788 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Nephronophthisis 4 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.042
DANN	Benign	0.22
PhyloP100		-4.9
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)		0.0		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: rs868163; hg19: chr1-5934490; COSMIC: COSV65397189; COSMIC: COSV65397189;