rs34248917

Variant names:

• chr1-5890953-C-T
• rs34248917
• NM_015102.5:c.2219G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-5890953-C-T
• chr1-5890953-C-A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_015102.5(NPHP4):​c.2219G>A​(p.Arg740His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0293 in 1,602,776 control chromosomes in the GnomAD database, including 782 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R740C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.022 (75 hom., cov: 33)
  • Exomes 𝑓: 0.030 (707 hom.)
• Consequence: NPHP4 NM_015102.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: -0.523
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006297469).
• BP6: Variant 1-5890953-C-T is Benign according to our data. Variant chr1-5890953-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 240967.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0223 (3388/152252) while in subpopulation NFE AF = 0.0327 (2222/68012). AF 95% confidence interval is 0.0315. There are 75 homozygotes in GnomAd4. There are 1678 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 75 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.2219G>A	p.Arg740His	missense	Exon 17 of 30	NP_055917.1	O75161-1
	NPHP4	NM_001291594.2		c.683G>A	p.Arg228His	missense	Exon 13 of 26	NP_001278523.1
	NPHP4	NM_001291593.2		c.680G>A	p.Arg227His	missense	Exon 14 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.2219G>A	p.Arg740His	missense	Exon 17 of 30	ENSP00000367398.4	O75161-1
	NPHP4	ENST00000378169.7	TSL:1	n.*1120G>A		non_coding_transcript_exon	Exon 14 of 27	ENSP00000367411.3	D6RA06
	NPHP4	ENST00000466897.1	TSL:1	n.296G>A		non_coding_transcript_exon	Exon 3 of 6	ENSP00000425745.1	H0YA08

Frequencies

GnomAD3 genomes AF: 0.0223 AC: 3389 AN: 152134 Hom.: 75 Cov.: 33

Gnomad AFR AF: 0.00569

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.0156

Gnomad ASJ AF: 0.0452

Gnomad EAS AF: 0.000773

Gnomad SAS AF: 0.0238

Gnomad FIN AF: 0.0323

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0327

Gnomad OTH AF: 0.0220

GnomAD2 exomes AF: 0.0247 AC: 5916 AN: 239630 AF XY: 0.0255

Gnomad AFR exome AF: 0.00500

Gnomad AMR exome AF: 0.00994

Gnomad ASJ exome AF: 0.0353

Gnomad EAS exome AF: 0.000344

Gnomad FIN exome AF: 0.0354

Gnomad NFE exome AF: 0.0326

Gnomad OTH exome AF: 0.0258

GnomAD4 exome AF: 0.0300 AC: 43532 AN: 1450524 Hom.: 707 Cov.: 31 AF XY: 0.0300 AC XY: 21604 AN XY: 719656

African (AFR) AF: 0.00486 AC: 162 AN: 33308

American (AMR) AF: 0.0102 AC: 451 AN: 44186

Ashkenazi Jewish (ASJ) AF: 0.0366 AC: 949 AN: 25940

East Asian (EAS) AF: 0.000483 AC: 19 AN: 39316

South Asian (SAS) AF: 0.0251 AC: 2139 AN: 85150

European-Finnish (FIN) AF: 0.0386 AC: 2033 AN: 52708

Middle Eastern (MID) AF: 0.0164 AC: 94 AN: 5742

European-Non Finnish (NFE) AF: 0.0326 AC: 36045 AN: 1104302

Other (OTH) AF: 0.0274 AC: 1640 AN: 59872

GnomAD4 genome AF: 0.0223 AC: 3388 AN: 152252 Hom.: 75 Cov.: 33 AF XY: 0.0225 AC XY: 1678 AN XY: 74440

African (AFR) AF: 0.00568 AC: 236 AN: 41564

American (AMR) AF: 0.0156 AC: 239 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0452 AC: 157 AN: 3472

East Asian (EAS) AF: 0.000775 AC: 4 AN: 5160

South Asian (SAS) AF: 0.0236 AC: 114 AN: 4822

European-Finnish (FIN) AF: 0.0323 AC: 342 AN: 10594

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0327 AC: 2222 AN: 68012

Other (OTH) AF: 0.0217 AC: 46 AN: 2116

Alfa AF: 0.0282 Hom.: 188

Bravo AF: 0.0194

TwinsUK AF: 0.0294 AC: 109

ALSPAC AF: 0.0319 AC: 123

ESP6500AA AF: 0.00479 AC: 19

ESP6500EA AF: 0.0335 AC: 278

ExAC AF: 0.0248 AC: 3001

Asia WGS AF: 0.00808 AC: 28 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Atypical hemolytic-uremic syndrome (1)
-	1	-	Bardet-Biedl syndrome (1)
-	-	1	Nephronophthisis (1)
-	-	1	Nephronophthisis 4 (1)
-	-	1	not provided (1)
-	-	1	Senior-Loken syndrome 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	0.087
DANN	Benign	0.70
DEOGEN2	Benign	0.15	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.037	N
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0063	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.32	N
PhyloP100		-0.52
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.42	N
REVEL	Benign	0.24
Sift	Benign	0.53	T
Sift4G	Benign	0.37	T
Polyphen		0.016	B
Vest4		0.13
MPC		0.086
ClinPred		0.0037	T
GERP RS		-7.2
Varity_R		0.025
gMVP		0.28
Mutation Taster		=96/4	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: rs34248917; hg19: chr1-5951013; COSMIC: COSV65394919;