rs1509419

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001128178.3(NPHP1):c.1353-47T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0182 in 1,111,680 control chromosomes in the GnomAD database, including 2,200 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.073 ( 1319 hom., cov: 32)

Exomes 𝑓: 0.0095 ( 881 hom. )

Consequence

NPHP1
NM_001128178.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.414

Publications

1 publications found

Variant links:

Genes affected

NPHP1 (HGNC:7905): (nephrocystin 1) This gene encodes a protein with src homology domain 3 (SH3) patterns. This protein interacts with Crk-associated substrate, and it appears to function in the control of cell division, as well as in cell-cell and cell-matrix adhesion signaling, likely as part of a multifunctional complex localized in actin- and microtubule-based structures. Mutations in this gene cause familial juvenile nephronophthisis type 1, a kidney disorder involving both tubules and glomeruli. Defects in this gene are also associated with Senior-Loken syndrome type 1, also referred to as juvenile nephronophthisis with Leber amaurosis, which is characterized by kidney and eye disease, and with Joubert syndrome type 4, which is characterized by cerebellar ataxia, oculomotor apraxia, psychomotor delay and neonatal breathing abnormalities, sometimes including retinal dystrophy and renal disease. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

NPHP1 Gene-Disease associations (from GenCC):

Joubert syndrome with renal defect
Inheritance: AR Classification: DEFINITIVE, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, G2P
nephronophthisis 1
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), G2P
Bardet-Biedl syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Senior-Loken syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

NPHP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BP6

Variant 2-110144616-A-G is Benign according to our data. Variant chr2-110144616-A-G is described in ClinVar as Benign. ClinVar VariationId is 255707.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.245 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001128178.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NPHP1	NM_001128178.3	MANE Select	c.1353-47T>C	intron	N/A	NP_001121650.1	O15259-2
NPHP1	NM_000272.5		c.1521-47T>C	intron	N/A	NP_000263.2
NPHP1	NM_207181.4		c.1518-47T>C	intron	N/A	NP_997064.2	O15259-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NPHP1	ENST00000445609.7	TSL:1 MANE Select	c.1353-47T>C	intron	N/A	ENSP00000389879.3	O15259-2
NPHP1	ENST00000316534.8	TSL:1	c.1521-47T>C	intron	N/A	ENSP00000313169.4	O15259-4
NPHP1	ENST00000393272.7	TSL:1	c.1518-47T>C	intron	N/A	ENSP00000376953.3	O15259-1

Frequencies

GnomAD3 genomes

AF:

0.0729

AC:

11087

AN:

152134

Hom.:

1317

Cov.:

show subpopulations

Gnomad AFR

AF:

0.249

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0304

Gnomad ASJ

AF:

0.0176

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.000566

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00143

Gnomad OTH

AF:

0.0637

GnomAD2 exomes

AF:

0.0200

AC:

4896

AN:

245254

AF XY:

0.0150

show subpopulations

Gnomad AFR exome

AF:

0.257

Gnomad AMR exome

AF:

0.0142

Gnomad ASJ exome

AF:

0.0166

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000421

Gnomad NFE exome

AF:

0.00164

Gnomad OTH exome

AF:

0.0105

GnomAD4 exome

AF:

0.00954

AC:

9150

AN:

959428

Hom.:

881

Cov.:

AF XY:

0.00802

AC XY:

4008

AN XY:

499640

show subpopulations

African (AFR)

AF:

0.261

AC:

6337

AN:

24302

American (AMR)

AF:

0.0152

AC:

669

AN:

43974

Ashkenazi Jewish (ASJ)

AF:

0.0158

AC:

363

AN:

22910

East Asian (EAS)

AF:

0.00

AC:

AN:

37194

South Asian (SAS)

AF:

0.000670

AC:

AN:

76076

European-Finnish (FIN)

AF:

0.000586

AC:

AN:

52872

Middle Eastern (MID)

AF:

0.0197

AC:

AN:

4166

European-Non Finnish (NFE)

AF:

0.00106

AC:

696

AN:

654232

Other (OTH)

AF:

0.0211

AC:

921

AN:

43702

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

395

791

1186

1582

1977

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

288

432

576

720

<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:

0.0730

AC:

11109

AN:

152252

Hom.:

1319

Cov.:

AF XY:

0.0707

AC XY:

5264

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.249

AC:

10340

AN:

41516

American (AMR)

AF:

0.0304

AC:

465

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0176

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000622

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000566

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00141

AC:

AN:

68032

Other (OTH)

AF:

0.0630

AC:

133

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

432

865

1297

1730

2162

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

200

300

400

500

<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:

0.0356

Hom.:

252

Bravo

AF:

0.0822

Asia WGS

AF:

0.0160

AC:

AN:

3476

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.19

(source)

DANN

Benign

0.42

PhyloP100

-0.41

Mutation Taster

=100/0

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

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