Genetic Variant NM_015102.5:c.3243G>C (chr1-5873324-C-G) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_015102.5(NPHP4):c.3243G>C(p.Gly1081Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0232 in 1,613,720 control chromosomes in the GnomAD database, including 548 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.016 ( 34 hom., cov: 33)

Exomes 𝑓: 0.024 ( 514 hom. )

Consequence

NPHP4
NM_015102.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.00100

Publications

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

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=-0.81).

BP6

Variant 1-5873324-C-G is Benign according to our data. Variant chr1-5873324-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.001 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0162 (2474/152292) while in subpopulation NFE AF = 0.0255 (1731/68006). AF 95% confidence interval is 0.0245. There are 34 homozygotes in GnomAd4. There are 1116 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 34 AR gene

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
NPHP4	NM_015102.5	MANE Select	c.3243G>C	p.Gly1081Gly	synonymous	Exon 23 of 30	NP_055917.1
NPHP4	NM_001291594.2		c.1707G>C	p.Gly569Gly	synonymous	Exon 19 of 26	NP_001278523.1
NPHP4	NM_001291593.2		c.1704G>C	p.Gly568Gly	synonymous	Exon 20 of 27	NP_001278522.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NPHP4	ENST00000378156.9	TSL:1 MANE Select	c.3243G>C	p.Gly1081Gly	synonymous	Exon 23 of 30	ENSP00000367398.4
NPHP4	ENST00000378169.7	TSL:1	n.*2144G>C		non_coding_transcript_exon	Exon 20 of 27	ENSP00000367411.3
NPHP4	ENST00000489180.6	TSL:2	n.*1054G>C		non_coding_transcript_exon	Exon 26 of 33	ENSP00000423747.1

Frequencies

GnomAD3 genomes

AF:

0.0163

AC:

2474

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00736

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0186

Gnomad ASJ

AF:

0.0170

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00462

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0255

Gnomad OTH

AF:

0.0177

GnomAD2 exomes

AF:

0.0145

AC:

3621

AN:

249198

AF XY:

0.0146

show subpopulations

Gnomad AFR exome

AF:

0.00684

Gnomad AMR exome

AF:

0.0110

Gnomad ASJ exome

AF:

0.0192

Gnomad EAS exome

AF:

0.0000556

Gnomad FIN exome

AF:

0.00571

Gnomad NFE exome

AF:

0.0236

Gnomad OTH exome

AF:

0.0185

GnomAD4 exome

AF:

0.0239

AC:

34953

AN:

1461428

Hom.:

514

Cov.:

AF XY:

0.0231

AC XY:

16797

AN XY:

726996

show subpopulations

African (AFR)

AF:

0.00585

AC:

196

AN:

33476

American (AMR)

AF:

0.0118

AC:

526

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.0194

AC:

506

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00119

AC:

103

AN:

86256

European-Finnish (FIN)

AF:

0.00545

AC:

291

AN:

53402

Middle Eastern (MID)

AF:

0.0160

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0286

AC:

31811

AN:

1111624

Other (OTH)

AF:

0.0237

AC:

1428

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

1605

3210

4814

6419

8024

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1250

2500

3750

5000

6250

<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:

0.0162

AC:

2474

AN:

152292

Hom.:

Cov.:

AF XY:

0.0150

AC XY:

1116

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.00734

AC:

305

AN:

41560

American (AMR)

AF:

0.0186

AC:

284

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.0170

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000829

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00462

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0255

AC:

1731

AN:

68006

Other (OTH)

AF:

0.0175

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

124

248

371

495

619

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

136

170

<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:

0.0235

Hom.:

Bravo

AF:

0.0175

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0255

EpiControl

AF:

0.0269

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

Kidney disorder (1)

Nephronophthisis (1)

Nephronophthisis 4 (1)

not provided (1)

Senior-Loken syndrome 4 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.88

(source)

DANN

Benign

0.47

PhyloP100

-0.0010

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

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