rs113097479

Variant names:

• chr1-5877229-T-C
• rs113097479
• NM_015102.5:c.2681A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015102.5(NPHP4):​c.2681A>G​(p.His894Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000656 in 1,608,998 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (2 hom., cov: 35)
  • Exomes 𝑓: 0.00033 (3 hom.)
• Consequence: NPHP4 NM_015102.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.466
• Publications: 6 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0034188628).
• BP6: Variant 1-5877229-T-C is Benign according to our data. Variant chr1-5877229-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 462717.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00377 (575/152378) while in subpopulation AFR AF = 0.0136 (564/41604). AF 95% confidence interval is 0.0126. There are 2 homozygotes in GnomAd4. There are 265 alleles in the male GnomAd4 subpopulation. Median coverage is 35. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

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.2681A>G	p.His894Arg	missense	Exon 20 of 30	NP_055917.1	O75161-1
	NPHP4	NM_001291594.2		c.1145A>G	p.His382Arg	missense	Exon 16 of 26	NP_001278523.1
	NPHP4	NM_001291593.2		c.1142A>G	p.His381Arg	missense	Exon 17 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.2681A>G	p.His894Arg	missense	Exon 20 of 30	ENSP00000367398.4	O75161-1
	NPHP4	ENST00000378169.7	TSL:1	n.*1582A>G		non_coding_transcript_exon	Exon 17 of 27	ENSP00000367411.3	D6RA06
	NPHP4	ENST00000489180.6	TSL:2	n.*229A>G		non_coding_transcript_exon	Exon 21 of 33	ENSP00000423747.1	O75161-2

Frequencies

GnomAD3 genomes AF: 0.00377 AC: 574 AN: 152262 Hom.: 2 Cov.: 35

Gnomad AFR AF: 0.0136

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000804 AC: 194 AN: 241362 AF XY: 0.000608

Gnomad AFR exome AF: 0.0121

Gnomad AMR exome AF: 0.000384

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000568

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000919

Gnomad OTH exome AF: 0.000340

GnomAD4 exome AF: 0.000330 AC: 481 AN: 1456620 Hom.: 3 Cov.: 35 AF XY: 0.000298 AC XY: 216 AN XY: 724044

African (AFR) AF: 0.0117 AC: 392 AN: 33408

American (AMR) AF: 0.000541 AC: 24 AN: 44350

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26026

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39526

South Asian (SAS) AF: 0.0000468 AC: 4 AN: 85448

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52966

Middle Eastern (MID) AF: 0.000696 AC: 4 AN: 5744

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1109032

Other (OTH) AF: 0.000915 AC: 55 AN: 60120

GnomAD4 genome AF: 0.00377 AC: 575 AN: 152378 Hom.: 2 Cov.: 35 AF XY: 0.00356 AC XY: 265 AN XY: 74518

African (AFR) AF: 0.0136 AC: 564 AN: 41604

American (AMR) AF: 0.000457 AC: 7 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68030

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.00152 Hom.: 3

Bravo AF: 0.00425

ESP6500AA AF: 0.0120 AC: 50

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00109 AC: 132

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Nephronophthisis (1)
-	-	1	Nephronophthisis 4 (1)
-	-	1	Senior-Loken syndrome 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	0.14
DANN	Benign	0.21
DEOGEN2	Benign	0.12	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0081	N
LIST_S2	Benign	0.48	T
MetaRNN	Benign	0.0034	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	0.92	L
PhyloP100		-0.47
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.22
Sift	Benign	0.72	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.082
MVP		0.67
MPC		0.076
ClinPred		0.0067	T
GERP RS		-9.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.039
gMVP		0.16
Mutation Taster		=88/12	polymorphism

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: rs113097479; hg19: chr1-5937289;