rs12093500

chr1-5905764-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015102.5(NPHP4):c.1631C>G(p.Ala544Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00587 in 1,609,506 control chromosomes in the GnomAD database, including 313 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A544A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.026 (141 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (172 hom.)
• Consequence: NPHP4 NM_015102.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.46

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016799569).
• BP6: Variant 1-5905764-G-C is Benign according to our data. Variant chr1-5905764-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 260545.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-5905764-G-C is described in Lovd as [Benign]. Variant chr1-5905764-G-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0851 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPHP4	NM_015102.5	c.1631C>G	p.Ala544Gly	missense_variant	14/30	ENST00000378156.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPHP4	ENST00000378156.9	c.1631C>G	p.Ala544Gly	missense_variant	14/30	1	NM_015102.5	P2

Frequencies

GnomAD3 genomes AF: 0.0261 AC: 3976 AN: 152124 Hom.: 142 Cov.: 32

Gnomad AFR AF: 0.0877

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0140

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.00112

Gnomad OTH AF: 0.0202

GnomAD3 exomes AF: 0.00771 AC: 1850 AN: 239812 Hom.: 51 AF XY: 0.00628 AC XY: 816 AN XY: 129966

Gnomad AFR exome AF: 0.0944

Gnomad AMR exome AF: 0.00826

Gnomad ASJ exome AF: 0.00112

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000341

Gnomad FIN exome AF: 0.0000474

Gnomad NFE exome AF: 0.00153

Gnomad OTH exome AF: 0.00665

GnomAD4 exome AF: 0.00375 AC: 5462 AN: 1457264 Hom.: 172 Cov.: 32 AF XY: 0.00345 AC XY: 2501 AN XY: 724424

Gnomad4 AFR exome AF: 0.0943

Gnomad4 AMR exome AF: 0.00896

Gnomad4 ASJ exome AF: 0.00123

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000410

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.00120

Gnomad4 OTH exome AF: 0.00745

GnomAD4 genome AF: 0.0261 AC: 3979 AN: 152242 Hom.: 141 Cov.: 32 AF XY: 0.0243 AC XY: 1813 AN XY: 74458

Gnomad4 AFR AF: 0.0875

Gnomad4 AMR AF: 0.0139

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00112

Gnomad4 OTH AF: 0.0199

Alfa AF: 0.00492 Hom.: 16

Bravo AF: 0.0299

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.0787 AC: 306

ESP6500EA AF: 0.00169 AC: 14

ExAC AF: 0.00857 AC: 1035

Asia WGS AF: 0.00491 AC: 18 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Kidney disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 12, 2016

- -

Senior-Loken syndrome 4 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Nephronophthisis Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 26, 2024

- -

Nephronophthisis 4 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	9.5
Dann	Benign	0.15
DEOGEN2	Benign	0.062	T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.0029	N
LIST_S2	Benign	0.31	T;T
MetaRNN	Benign	0.0017	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.7	N;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.41	N;.
REVEL	Benign	0.25
Sift	Benign	1.0	T;.
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;.
Vest4		0.039
MVP		0.77
MPC		0.064
ClinPred		0.0018	T
GERP RS		4.5
Varity_R		0.037
gMVP		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs12093500; hg19: chr1-5965824; COSMIC: COSV65396463; COSMIC: COSV65396463;