NM_138694.4:c.9237G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_138694.4(PKHD1):c.9237G>A(p.Ala3079Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.382 in 1,613,552 control chromosomes in the GnomAD database, including 124,516 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.32 ( 9635 hom., cov: 32)

Exomes 𝑓: 0.39 ( 114881 hom. )

Consequence

PKHD1
NM_138694.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 1.61

Publications

20 publications found

Variant links:

Genes affected

PKHD1 (HGNC:9016): (PKHD1 ciliary IPT domain containing fibrocystin/polyductin) The protein encoded by this gene is predicted to have a single transmembrane (TM)-spanning domain and multiple copies of an immunoglobulin-like plexin-transcription-factor domain. Alternative splicing results in two transcript variants encoding different isoforms. Other alternatively spliced transcripts have been described, but the full length sequences have not been determined. Several of these transcripts are predicted to encode truncated products which lack the TM and may be secreted. Mutations in this gene cause autosomal recessive polycystic kidney disease, also known as polycystic kidney and hepatic disease-1. [provided by RefSeq, Jul 2008]

PKHD1 Gene-Disease associations (from GenCC):

autosomal recessive polycystic kidney disease
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Myriad Women’s Health, Orphanet
polycystic kidney disease 4
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine, Genomics England PanelApp
Caroli disease
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PKHD1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.36).

BP6

Variant 6-51748379-C-T is Benign according to our data. Variant chr6-51748379-C-T is described in ClinVar as Benign. ClinVar VariationId is 96441.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.61 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.658 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKHD1	NM_138694.4 link	c.9237G>A	p.Ala3079Ala	synonymous_variant	Exon 58 of 67	ENST00000371117.8	NP_619639.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8 link	c.9237G>A	p.Ala3079Ala	synonymous_variant	Exon 58 of 67	1	NM_138694.4	ENSP00000360158.3
PKHD1	ENST00000340994.4 link	c.9237G>A	p.Ala3079Ala	synonymous_variant	Exon 58 of 61	5		ENSP00000341097.4

Frequencies

GnomAD3 genomes

AF:

0.320

AC:

48581

AN:

151888

Hom.:

9638

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0949

Gnomad AMI

AF:

0.364

Gnomad AMR

AF:

0.459

Gnomad ASJ

AF:

0.311

Gnomad EAS

AF:

0.676

Gnomad SAS

AF:

0.505

Gnomad FIN

AF:

0.418

Gnomad MID

AF:

0.225

Gnomad NFE

AF:

0.371

Gnomad OTH

AF:

0.317

GnomAD2 exomes

AF:

0.420

AC:

105415

AN:

251078

AF XY:

0.422

show subpopulations

Gnomad AFR exome

AF:

0.0865

Gnomad AMR exome

AF:

0.572

Gnomad ASJ exome

AF:

0.331

Gnomad EAS exome

AF:

0.711

Gnomad FIN exome

AF:

0.421

Gnomad NFE exome

AF:

0.365

Gnomad OTH exome

AF:

0.375

GnomAD4 exome

AF:

0.388

AC:

567344

AN:

1461544

Hom.:

114881

Cov.:

AF XY:

0.391

AC XY:

284371

AN XY:

727090

show subpopulations

African (AFR)

AF:

0.0802

AC:

2683

AN:

33468

American (AMR)

AF:

0.555

AC:

24792

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.322

AC:

8415

AN:

26134

East Asian (EAS)

AF:

0.661

AC:

26235

AN:

39696

South Asian (SAS)

AF:

0.494

AC:

42645

AN:

86252

European-Finnish (FIN)

AF:

0.421

AC:

22503

AN:

53400

Middle Eastern (MID)

AF:

0.294

AC:

1695

AN:

5768

European-Non Finnish (NFE)

AF:

0.374

AC:

415754

AN:

1111738

Other (OTH)

AF:

0.375

AC:

22622

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

20358

40717

61075

81434

101792

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13292

26584

39876

53168

66460

<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:

0.320

AC:

48573

AN:

152008

Hom.:

9635

Cov.:

AF XY:

0.331

AC XY:

24561

AN XY:

74264

show subpopulations

African (AFR)

AF:

0.0947

AC:

3932

AN:

41508

American (AMR)

AF:

0.459

AC:

7007

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.311

AC:

1077

AN:

3468

East Asian (EAS)

AF:

0.676

AC:

3485

AN:

5152

South Asian (SAS)

AF:

0.504

AC:

2427

AN:

4814

European-Finnish (FIN)

AF:

0.418

AC:

4400

AN:

10534

Middle Eastern (MID)

AF:

0.211

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.371

AC:

25190

AN:

67960

Other (OTH)

AF:

0.315

AC:

663

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1529

3059

4588

6118

7647

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

480

960

1440

1920

2400

<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:

0.352

Hom.:

38473

Bravo

AF:

0.311

Asia WGS

AF:

0.475

AC:

1654

AN:

3478

EpiCase

AF:

0.362

EpiControl

AF:

0.362

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Oct 27, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Polycystic kidney disease

Benign:2

May 20, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

The PKHD1 p.Ala3079= variant was identified in dbSNP (ID: rs765525) â€šÃ„ÃºWith Benign alleleâ€šÃ„Ã¹, ClinVar (classified benign by EGL Genetic Diagnostics (Eurofins Clinical Diagnostics), Prevention Genetics, Illumina), Clinvitae (3x), RWTH AAachen University ARPKD database (as a polymorphism) and in control databases in 113331 (26391 homozygous) of 276718 chromosomes at a frequency of 0.4 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 2095 (96 homozygous) of 24010 chromosomes (freq: 0.09), Other in 2490 (481 homozygous) of 6458 chromosomes (freq: 0.4), Latino in 19685 (5835 homozygous) of 34372 chromosomes (freq: 0.6), European Non-Finnish in 46358 (8579 homozygous) of 126354 chromosomes (freq: 0.4), Ashkenazi Jewish in 3338 (532 homozygous) of 10138 chromosomes (freq: 0.3), East Asian in 13406 (4748 homozygous) of 18840 chromosomes (freq: 0.7), European Finnish in 10817 (2293 homozygous) of 25772 chromosomes (freq: 0.4), and South Asian in 15142 (3827 homozygous) of 30774 chromosomes (freq: 0.5). The variant was not identified in the GeneInsight-COGR, or LOVD 3.0. The p.Ala3079= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory criteria to be classified as benign. -

Autosomal recessive polycystic kidney disease

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Polycystic kidney disease 4

Benign:2

Jun 19, 2021

Pars Genome Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Jul 09, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.36

CADD

Benign

8.1

(source)

DANN

Benign

0.62

PhyloP100

1.6

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over