rs12120967

Variant names:

• chr1-5905321-C-T
• rs12120967
• NM_015102.5:c.1926G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-5905321-C-T
• chr1-5905321-C-G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_015102.5(NPHP4):​c.1926G>A​(p.Glu642Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.152 in 1,612,892 control chromosomes in the GnomAD database, including 19,853 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1356 hom., cov: 33)
  • Exomes 𝑓: 0.16 (18497 hom.)
• Consequence: NPHP4 NM_015102.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.740
• Publications: 19 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: ClinGen, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• Senior-Loken syndrome 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 1-5905321-C-T is Benign according to our data. Variant chr1-5905321-C-T is described in ClinVar as Benign. ClinVar VariationId is 95673.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.74 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.163 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHP4	NM_015102.5	MANE Select	c.1926G>A	p.Glu642Glu	synonymous	Exon 15 of 30	NP_055917.1	O75161-1
	NPHP4	NM_001291594.2		c.390G>A	p.Glu130Glu	synonymous	Exon 11 of 26	NP_001278523.1
	NPHP4	NM_001291593.2		c.387G>A	p.Glu129Glu	synonymous	Exon 12 of 27	NP_001278522.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHP4	ENST00000378156.9	TSL:1 MANE Select	c.1926G>A	p.Glu642Glu	synonymous	Exon 15 of 30	ENSP00000367398.4	O75161-1
	NPHP4	ENST00000378169.7	TSL:1	n.*827G>A		non_coding_transcript_exon	Exon 12 of 27	ENSP00000367411.3	D6RA06
	NPHP4	ENST00000466897.1	TSL:1	n.3G>A		non_coding_transcript_exon	Exon 1 of 6	ENSP00000425745.1	H0YA08

Frequencies

GnomAD3 genomes AF: 0.118 AC: 17947 AN: 152132 Hom.: 1357 Cov.: 33

Gnomad AFR AF: 0.0328

Gnomad AMI AF: 0.160

Gnomad AMR AF: 0.114

Gnomad ASJ AF: 0.222

Gnomad EAS AF: 0.0743

Gnomad SAS AF: 0.119

Gnomad FIN AF: 0.131

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.166

Gnomad OTH AF: 0.136

GnomAD2 exomes AF: 0.132 AC: 32824 AN: 249286 AF XY: 0.135

Gnomad AFR exome AF: 0.0271

Gnomad AMR exome AF: 0.0767

Gnomad ASJ exome AF: 0.220

Gnomad EAS exome AF: 0.0768

Gnomad FIN exome AF: 0.136

Gnomad NFE exome AF: 0.167

Gnomad OTH exome AF: 0.145

GnomAD4 exome AF: 0.155 AC: 226534 AN: 1460642 Hom.: 18497 Cov.: 32 AF XY: 0.155 AC XY: 112298 AN XY: 726642

African (AFR) AF: 0.0263 AC: 881 AN: 33478

American (AMR) AF: 0.0816 AC: 3649 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.217 AC: 5672 AN: 26130

East Asian (EAS) AF: 0.0765 AC: 3035 AN: 39696

South Asian (SAS) AF: 0.115 AC: 9899 AN: 86240

European-Finnish (FIN) AF: 0.141 AC: 7513 AN: 53398

Middle Eastern (MID) AF: 0.137 AC: 790 AN: 5768

European-Non Finnish (NFE) AF: 0.167 AC: 185870 AN: 1110888

Other (OTH) AF: 0.153 AC: 9225 AN: 60334

GnomAD4 genome AF: 0.118 AC: 17940 AN: 152250 Hom.: 1356 Cov.: 33 AF XY: 0.117 AC XY: 8715 AN XY: 74440

African (AFR) AF: 0.0327 AC: 1357 AN: 41554

American (AMR) AF: 0.113 AC: 1736 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.222 AC: 772 AN: 3470

East Asian (EAS) AF: 0.0741 AC: 384 AN: 5184

South Asian (SAS) AF: 0.118 AC: 571 AN: 4822

European-Finnish (FIN) AF: 0.131 AC: 1383 AN: 10596

Middle Eastern (MID) AF: 0.139 AC: 41 AN: 294

European-Non Finnish (NFE) AF: 0.166 AC: 11265 AN: 68008

Other (OTH) AF: 0.135 AC: 285 AN: 2112

Alfa AF: 0.154 Hom.: 3266

Bravo AF: 0.113

Asia WGS AF: 0.100 AC: 346 AN: 3478

EpiCase AF: 0.180

EpiControl AF: 0.174

ClinVar

ClinVar submissions

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	-0.70
CADD	Benign	1.5
DANN	Benign	0.53
PhyloP100		-0.74
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: rs12120967; hg19: chr1-5965381; COSMIC: COSV65395162;