chr2-110161604-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_001128178.3(NPHP1):c.953C>T(p.Thr318Ile) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000146 in 1,592,154 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/24 in silico tools predict 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 0.00079 ( 2 hom., cov: 32)

Exomes 𝑓: 0.000078 ( 2 hom. )

Consequence

NPHP1
NM_001128178.3 missense, splice_region

Scores

Splicing: ADA: 0.003788

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:2

Conservation

PhyloP100: 4.97

Publications

0 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.020986646).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000788 (120/152216) while in subpopulation AFR AF = 0.00277 (115/41530). AF 95% confidence interval is 0.00236. There are 2 homozygotes in GnomAd4. There are 47 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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	HGVSp	Effect	Exon Rank	Protein	UniProt
NPHP1	NM_001128178.3	MANE Select	c.953C>T	p.Thr318Ile	missense splice_region	Exon 10 of 20	NP_001121650.1	O15259-2
NPHP1	NM_000272.5		c.1121C>T	p.Thr374Ile	missense splice_region	Exon 10 of 20	NP_000263.2
NPHP1	NM_207181.4		c.1118C>T	p.Thr373Ile	missense splice_region	Exon 10 of 20	NP_997064.2	O15259-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NPHP1	ENST00000445609.7	TSL:1 MANE Select	c.953C>T	p.Thr318Ile	missense splice_region	Exon 10 of 20	ENSP00000389879.3	O15259-2
NPHP1	ENST00000316534.8	TSL:1	c.1121C>T	p.Thr374Ile	missense splice_region	Exon 10 of 20	ENSP00000313169.4	O15259-4
NPHP1	ENST00000393272.7	TSL:1	c.1118C>T	p.Thr373Ile	missense splice_region	Exon 10 of 20	ENSP00000376953.3	O15259-1

Frequencies

GnomAD3 genomes

AF:

0.000782

AC:

119

AN:

152098

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00275

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.00

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.000231

AC:

AN:

250946

AF XY:

0.000177

show subpopulations

Gnomad AFR exome

AF:

0.00277

Gnomad AMR exome

AF:

0.000348

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000785

AC:

113

AN:

1439938

Hom.:

Cov.:

AF XY:

0.0000725

AC XY:

AN XY:

717118

show subpopulations

African (AFR)

AF:

0.00275

AC:

AN:

33106

American (AMR)

AF:

0.000291

AC:

AN:

44652

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25976

East Asian (EAS)

AF:

0.00

AC:

AN:

39494

South Asian (SAS)

AF:

0.0000234

AC:

AN:

85434

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53320

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5734

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1092600

Other (OTH)

AF:

0.000117

AC:

AN:

59622

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.000788

AC:

120

AN:

152216

Hom.:

Cov.:

AF XY:

0.000632

AC XY:

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.00277

AC:

115

AN:

41530

American (AMR)

AF:

0.000131

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10564

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68022

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000318

Hom.:

Bravo

AF:

0.00105

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000264

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Joubert syndrome with renal defect (2)

not provided (2)

Nephronophthisis (1)

Nephronophthisis 1 (1)

NPHP1-related disorder (1)

Senior-Loken syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

Eigen

Uncertain

0.28

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.60

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.021

MetaSVM

Uncertain

-0.014

MutationAssessor

Benign

1.7

PhyloP100

5.0

PrimateAI

Benign

0.32

PROVEAN

Benign

-2.3

REVEL

Benign

0.27

Sift

Benign

0.090

Sift4G

Benign

0.14

Polyphen

0.99

Vest4

0.39

MVP

0.91

MPC

0.38

ClinPred

0.054

GERP RS

4.4

Varity_R

0.12

gMVP

0.40

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0038

dbscSNV1_RF

Benign

0.024

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

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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