dbSNP rs199557439: NPHP4:p.Gln494Gln (chr1-5909173-C-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS1

The NM_015102.5(NPHP4):c.1482G>A(p.Gln494Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000998 in 1,602,526 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00058 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000049 ( 0 hom. )

Consequence

NPHP4
NM_015102.5 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 0.231

Publications

0 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: 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

NPHP4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.56).

BP6

Variant 1-5909173-C-T is Benign according to our data. Variant chr1-5909173-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 215517.

BP7

Synonymous conserved (PhyloP=0.231 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000585 (89/152220) while in subpopulation AFR AF = 0.00205 (85/41524). AF 95% confidence interval is 0.0017. There are 0 homozygotes in GnomAd4. There are 41 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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.1482G>A	p.Gln494Gln	synonymous	Exon 12 of 30	NP_055917.1	O75161-1
NPHP4	NM_001291594.2		c.76-3390G>A		intron	N/A	NP_001278523.1
NPHP4	NM_001291593.2		c.76-3393G>A		intron	N/A	NP_001278522.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NPHP4	ENST00000378156.9	TSL:1 MANE Select	c.1482G>A	p.Gln494Gln	synonymous	Exon 12 of 30	ENSP00000367398.4	O75161-1
NPHP4	ENST00000489180.6	TSL:2	n.1482G>A		non_coding_transcript_exon	Exon 12 of 33	ENSP00000423747.1	O75161-2
NPHP4	ENST00000378169.7	TSL:1	n.*516-3393G>A		intron	N/A	ENSP00000367411.3	D6RA06

Frequencies

GnomAD3 genomes

AF:

0.000572

AC:

AN:

152102

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00200

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

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:

0.00

GnomAD2 exomes

AF:

0.000114

AC:

AN:

227678

AF XY:

0.0000973

show subpopulations

Gnomad AFR exome

AF:

0.00172

Gnomad AMR exome

AF:

0.0000615

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000177

GnomAD4 exome

AF:

0.0000490

AC:

AN:

1450306

Hom.:

Cov.:

AF XY:

0.0000333

AC XY:

AN XY:

720026

show subpopulations

African (AFR)

AF:

0.00177

AC:

AN:

33318

American (AMR)

AF:

0.0000464

AC:

AN:

43126

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25888

East Asian (EAS)

AF:

0.0000508

AC:

AN:

39340

South Asian (SAS)

AF:

0.00

AC:

AN:

83440

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52570

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

9.03e-7

AC:

AN:

1106900

Other (OTH)

AF:

0.000100

AC:

AN:

59970

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000585

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.000551

AC XY:

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.00205

AC:

AN:

41524

American (AMR)

AF:

0.000261

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67992

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

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:

0.000592

Hom.:

Bravo

AF:

0.000635

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Nephronophthisis (1)

NPHP4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.56

CADD

Benign

1.6

(source)

DANN

Benign

0.35

PhyloP100

0.23

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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