rs890884615

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2PM5PP3PP5_Moderate

The NM_138694.4(PKHD1):c.931A>G(p.Thr311Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000437 in 1,602,536 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T311I) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000014 ( 0 hom., cov: 23)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

PKHD1
NM_138694.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 2.73

Publications

0 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: Likely_pathogenic. The variant received 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr6-52064999-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2711036.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.829

PP5

Variant 6-52065000-T-C is Pathogenic according to our data. Variant chr6-52065000-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 554720.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKHD1	NM_138694.4 link	c.931A>G	p.Thr311Ala	missense_variant	Exon 13 of 67	ENST00000371117.8	NP_619639.3	P08F94-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8 link	c.931A>G	p.Thr311Ala	missense_variant	Exon 13 of 67	1	NM_138694.4	ENSP00000360158.3		P08F94-1
PKHD1	ENST00000340994.4 link	c.931A>G	p.Thr311Ala	missense_variant	Exon 13 of 61	5		ENSP00000341097.4		P08F94-2

Frequencies

GnomAD3 genomes

AF:

0.0000136

AC:

AN:

146932

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000679

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:

0.0000149

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000159

AC:

AN:

250844

AF XY:

0.0000221

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000353

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000344

AC:

AN:

1455604

Hom.:

Cov.:

AF XY:

0.00000552

AC XY:

AN XY:

724332

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33092

American (AMR)

AF:

0.00

AC:

AN:

44590

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25900

East Asian (EAS)

AF:

0.00

AC:

AN:

38806

South Asian (SAS)

AF:

0.00

AC:

AN:

86166

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52770

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5724

European-Non Finnish (NFE)

AF:

0.00000361

AC:

AN:

1108592

Other (OTH)

AF:

0.0000167

AC:

AN:

59964

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

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:

0.0000136

AC:

AN:

146932

Hom.:

Cov.:

AF XY:

0.0000140

AC XY:

AN XY:

71432

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

39014

American (AMR)

AF:

0.0000679

AC:

AN:

14718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3438

East Asian (EAS)

AF:

0.00

AC:

AN:

5024

South Asian (SAS)

AF:

0.00

AC:

AN:

4512

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9770

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000149

AC:

AN:

67234

Other (OTH)

AF:

0.00

AC:

AN:

2012

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0296732), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

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:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Autosomal recessive polycystic kidney disease

Pathogenic:1

Jun 04, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is present in population databases (no rsID available, gnomAD 0.004%). This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 311 of the PKHD1 protein (p.Thr311Ala). This missense change has been observed in individual(s) with PKHD1-related conditions (PMID: 26385851). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 554720). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PKHD1 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Polycystic kidney disease 4

Uncertain:1

Nov 01, 2017

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

0.050

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.77

D;.

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.71

T;T

M_CAP

Uncertain

0.14

MetaRNN

Pathogenic

0.83

D;D

MetaSVM

Uncertain

0.28

MutationAssessor

Pathogenic

3.2

M;M

PhyloP100

2.7

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-3.4

D;D

REVEL

Uncertain

0.57

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.89

MutPred

0.52

Loss of glycosylation at T311 (P = 0.0084);Loss of glycosylation at T311 (P = 0.0084);

MVP

0.96

MPC

0.36

ClinPred

0.95

GERP RS

5.8

Varity_R

0.90

gMVP

0.80

Mutation Taster

=0/100

disease causing

(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