dbSNP rs151204566: NPHP1:c.1270-4C>T (chr2-110146839-G-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001128178.3(NPHP1):c.1270-4C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00258 in 1,608,944 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0018 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0027 ( 20 hom. )

Consequence

NPHP1
NM_001128178.3 splice_region, intron

Scores

Splicing: ADA: 0.0008444

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:8

Conservation

PhyloP100: 0.472

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.5).

BP6

Variant 2-110146839-G-A is Benign according to our data. Variant chr2-110146839-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 194327.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00181 (276/152178) while in subpopulation NFE AF = 0.00215 (146/68008). AF 95% confidence interval is 0.00186. There are 2 homozygotes in GnomAd4. There are 116 alleles in the male GnomAd4 subpopulation. Median coverage is 32. 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_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.1270-4C>T	splice_region intron	N/A	NP_001121650.1	O15259-2
NPHP1	NM_000272.5		c.1438-4C>T	splice_region intron	N/A	NP_000263.2
NPHP1	NM_207181.4		c.1435-4C>T	splice_region 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.1270-4C>T	splice_region intron	N/A	ENSP00000389879.3	O15259-2
NPHP1	ENST00000316534.8	TSL:1	c.1438-4C>T	splice_region intron	N/A	ENSP00000313169.4	O15259-4
NPHP1	ENST00000393272.7	TSL:1	c.1435-4C>T	splice_region intron	N/A	ENSP00000376953.3	O15259-1

Frequencies

GnomAD3 genomes

AF:

0.00182

AC:

276

AN:

152060

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000328

Gnomad ASJ

AF:

0.0314

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.0000945

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00215

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00249

AC:

626

AN:

251262

AF XY:

0.00253

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.000636

Gnomad ASJ exome

AF:

0.0270

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00221

Gnomad OTH exome

AF:

0.00261

GnomAD4 exome

AF:

0.00266

AC:

3882

AN:

1456766

Hom.:

Cov.:

AF XY:

0.00271

AC XY:

1962

AN XY:

725004

show subpopulations

African (AFR)

AF:

0.000420

AC:

AN:

33370

American (AMR)

AF:

0.000581

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0259

AC:

677

AN:

26098

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39640

South Asian (SAS)

AF:

0.00169

AC:

146

AN:

86154

European-Finnish (FIN)

AF:

0.0000375

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00191

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.00250

AC:

2765

AN:

1107402

Other (OTH)

AF:

0.00398

AC:

240

AN:

60226

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

173

347

520

694

867

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

124

248

372

496

620

<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:

0.00181

AC:

276

AN:

152178

Hom.:

Cov.:

AF XY:

0.00156

AC XY:

116

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.000193

AC:

AN:

41530

American (AMR)

AF:

0.000327

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.0314

AC:

109

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.000415

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0000945

AC:

AN:

10582

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00215

AC:

146

AN:

68008

Other (OTH)

AF:

0.00237

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00433

Hom.:

Bravo

AF:

0.00189

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00289

EpiControl

AF:

0.00207

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (2)

Joubert syndrome with renal defect (1)

Nephronophthisis (1)

Nephronophthisis 1 (1)

Senior-Loken syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Benign

0.68

PhyloP100

0.47

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00084

dbscSNV1_RF

Benign

0.022

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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