rs7520105

Variant names:

• chr1-5927636-T-C
• rs7520105
• NM_015102.5:c.1441+13A>G

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.1441+13A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.162 in 1,595,044 control chromosomes in the GnomAD database, including 21,666 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2301 hom., cov: 32)
  • Exomes 𝑓: 0.16 (19365 hom.)
• Consequence: NPHP4 NM_015102.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.540
• Publications: 5 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=-0.83).
• BP6: Variant 1-5927636-T-C is Benign according to our data. Variant chr1-5927636-T-C is described in ClinVar as Benign. ClinVar VariationId is 95671.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.211 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.1441+13A>G		intron	N/A	NP_055917.1
	NPHP4	NM_001291594.2		c.75+13A>G		intron	N/A	NP_001278523.1
	NPHP4	NM_001291593.2		c.75+13A>G		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.1441+13A>G		intron	N/A	ENSP00000367398.4
	NPHP4	ENST00000378169.7	TSL:1	n.*515+13A>G		intron	N/A	ENSP00000367411.3
	NPHP4	ENST00000489180.6	TSL:2	n.1441+13A>G		intron	N/A	ENSP00000423747.1

Frequencies

GnomAD3 genomes AF: 0.171 AC: 25985 AN: 152042 Hom.: 2301 Cov.: 32

Gnomad AFR AF: 0.215

Gnomad AMI AF: 0.160

Gnomad AMR AF: 0.134

Gnomad ASJ AF: 0.224

Gnomad EAS AF: 0.0751

Gnomad SAS AF: 0.122

Gnomad FIN AF: 0.130

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.167

Gnomad OTH AF: 0.184

GnomAD2 exomes AF: 0.145 AC: 35805 AN: 246092 AF XY: 0.146

Gnomad AFR exome AF: 0.210

Gnomad AMR exome AF: 0.0875

Gnomad ASJ exome AF: 0.221

Gnomad EAS exome AF: 0.0770

Gnomad FIN exome AF: 0.137

Gnomad NFE exome AF: 0.168

Gnomad OTH exome AF: 0.155

GnomAD4 exome AF: 0.161 AC: 232402 AN: 1442884 Hom.: 19365 Cov.: 32 AF XY: 0.160 AC XY: 114058 AN XY: 714284

African (AFR) AF: 0.215 AC: 7136 AN: 33150

American (AMR) AF: 0.0938 AC: 4154 AN: 44274

Ashkenazi Jewish (ASJ) AF: 0.218 AC: 5613 AN: 25746

East Asian (EAS) AF: 0.0765 AC: 3001 AN: 39204

South Asian (SAS) AF: 0.117 AC: 10018 AN: 85388

European-Finnish (FIN) AF: 0.141 AC: 7482 AN: 53154

Middle Eastern (MID) AF: 0.162 AC: 923 AN: 5688

European-Non Finnish (NFE) AF: 0.168 AC: 184174 AN: 1096786

Other (OTH) AF: 0.166 AC: 9901 AN: 59494

GnomAD4 genome AF: 0.171 AC: 26000 AN: 152160 Hom.: 2301 Cov.: 32 AF XY: 0.169 AC XY: 12547 AN XY: 74420

African (AFR) AF: 0.214 AC: 8895 AN: 41482

American (AMR) AF: 0.134 AC: 2043 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.224 AC: 778 AN: 3472

East Asian (EAS) AF: 0.0749 AC: 387 AN: 5166

South Asian (SAS) AF: 0.122 AC: 587 AN: 4826

European-Finnish (FIN) AF: 0.130 AC: 1380 AN: 10604

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.167 AC: 11355 AN: 67996

Other (OTH) AF: 0.182 AC: 384 AN: 2112

Alfa AF: 0.179 Hom.: 502

Bravo AF: 0.174

Asia WGS AF: 0.109 AC: 378 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	5.7
DANN	Benign	0.58
PhyloP100		0.54
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: rs7520105; hg19: chr1-5987696; COSMIC: COSV65395165;