dbSNP rs3747990: NPHP4:p.Ala881Ala (chr1-5877267-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_015102.5(NPHP4):c.2643G>A(p.Ala881Ala) 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 1,600,490 control chromosomes in the GnomAD database, including 19,880 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.12 ( 1382 hom., cov: 35)

Exomes 𝑓: 0.16 ( 18498 hom. )

Consequence

NPHP4
NM_015102.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -5.70

Publications

16 publications found

Variant links:

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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, ClinGen
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

NPHP4 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_015102.5, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.74).

BP6

Variant 1-5877267-C-T is Benign according to our data. Variant chr1-5877267-C-T is described in ClinVar as Benign. ClinVar VariationId is 95677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-5.7 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NPHP4	NM_015102.5	MANE Select	c.2643G>A	p.Ala881Ala	synonymous	Exon 20 of 30	NP_055917.1	O75161-1
NPHP4	NM_001291594.2		c.1107G>A	p.Ala369Ala	synonymous	Exon 16 of 26	NP_001278523.1
NPHP4	NM_001291593.2		c.1104G>A	p.Ala368Ala	synonymous	Exon 17 of 27	NP_001278522.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NPHP4	ENST00000378156.9	TSL:1 MANE Select	c.2643G>A	p.Ala881Ala	synonymous	Exon 20 of 30	ENSP00000367398.4	O75161-1
NPHP4	ENST00000378169.7	TSL:1	n.*1544G>A		non_coding_transcript_exon	Exon 17 of 27	ENSP00000367411.3	D6RA06
NPHP4	ENST00000489180.6	TSL:2	n.*191G>A		non_coding_transcript_exon	Exon 21 of 33	ENSP00000423747.1	O75161-2

Frequencies

GnomAD3 genomes

AF:

0.119

AC:

18101

AN:

152180

Hom.:

1383

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0326

Gnomad AMI

AF:

0.160

Gnomad AMR

AF:

0.114

Gnomad ASJ

AF:

0.229

Gnomad EAS

AF:

0.0751

Gnomad SAS

AF:

0.138

Gnomad FIN

AF:

0.131

Gnomad MID

AF:

0.130

Gnomad NFE

AF:

0.166

Gnomad OTH

AF:

0.140

GnomAD2 exomes

AF:

0.131

AC:

31812

AN:

242056

AF XY:

0.136

show subpopulations

Gnomad AFR exome

AF:

0.0258

Gnomad AMR exome

AF:

0.0747

Gnomad ASJ exome

AF:

0.223

Gnomad EAS exome

AF:

0.0740

Gnomad FIN exome

AF:

0.136

Gnomad NFE exome

AF:

0.163

Gnomad OTH exome

AF:

0.148

GnomAD4 exome

AF:

0.156

AC:

225883

AN:

1448192

Hom.:

18498

Cov.:

AF XY:

0.155

AC XY:

111683

AN XY:

718344

show subpopulations

African (AFR)

AF:

0.0258

AC:

860

AN:

33328

American (AMR)

AF:

0.0811

AC:

3585

AN:

44198

Ashkenazi Jewish (ASJ)

AF:

0.221

AC:

5729

AN:

25916

East Asian (EAS)

AF:

0.0763

AC:

2996

AN:

39266

South Asian (SAS)

AF:

0.133

AC:

11300

AN:

85230

European-Finnish (FIN)

AF:

0.142

AC:

7512

AN:

53064

Middle Eastern (MID)

AF:

0.154

AC:

883

AN:

5718

European-Non Finnish (NFE)

AF:

0.167

AC:

183726

AN:

1101784

Other (OTH)

AF:

0.156

AC:

9292

AN:

59688

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

9270

18541

27811

37082

46352

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6454

12908

19362

25816

32270

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.119

AC:

18095

AN:

152298

Hom.:

1382

Cov.:

AF XY:

0.118

AC XY:

8794

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.0325

AC:

1352

AN:

41590

American (AMR)

AF:

0.114

AC:

1742

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.229

AC:

796

AN:

3472

East Asian (EAS)

AF:

0.0749

AC:

387

AN:

5166

South Asian (SAS)

AF:

0.138

AC:

666

AN:

4828

European-Finnish (FIN)

AF:

0.131

AC:

1390

AN:

10616

Middle Eastern (MID)

AF:

0.139

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.166

AC:

11282

AN:

67996

Other (OTH)

AF:

0.138

AC:

293

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

843

1685

2528

3370

4213

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

204

408

612

816

1020

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.156

Hom.:

3263

Bravo

AF:

0.113

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

Nephronophthisis 4 (2)

not provided (2)

Nephronophthisis (1)

Senior-Loken syndrome 4 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.74

CADD

Benign

0.47

(source)

DANN

Benign

0.59

PhyloP100

-5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over