rs1343246818

Positions:

chr6-51748092-T-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong

The ENST00000371117.8(PKHD1):c.9524A>G(p.Asn3175Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000496 in 1,613,920 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N3175D) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

PKHD1
ENST00000371117.8 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 5.23

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in ENST00000371117.8

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.988

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKHD1	NM_138694.4 linkuse as main transcript	c.9524A>G	p.Asn3175Ser	missense_variant	58/67	ENST00000371117.8	NP_619639.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8 linkuse as main transcript	c.9524A>G	p.Asn3175Ser	missense_variant	58/67	1	NM_138694.4	ENSP00000360158	P2	P08F94-1
PKHD1	ENST00000340994.4 linkuse as main transcript	c.9524A>G	p.Asn3175Ser	missense_variant	58/61	5		ENSP00000341097	A2	P08F94-2

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461702

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727166

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 13, 2024

Variant summary: PKHD1 c.9524A>G (p.Asn3175Ser) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250864 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.9524A>G has been reported in the literature in individual affected with Polycystic Kidney And Hepatic Disease (Furu_2003). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 12874454). ClinVar contains an entry for this variant (Variation ID: 550173). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Autosomal recessive polycystic kidney disease

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Dec 21, 2016

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 30, 2023

Observed in the heterozygous state in an individual with childhood-onset nephromegaly and systemic hypertension in published literature (Furu et al., 2003); Reported in heterozygous parents of child with autosomal recessive polycystic kidney disease in unrelated families in published literature (Bitarafan et al., 2018); however, genetic testing was never performed on the affected children; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30595564, 12874454) -

Polycystic kidney disease 4

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Uncertain

0.065

BayesDel_noAF

Benign

-0.14

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.65

D;.

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.88

D;D

M_CAP

Uncertain

0.14

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Uncertain

0.45

MutationAssessor

Uncertain

2.5

M;M

MutationTaster

Benign

0.85

D;D

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-4.0

D;D

REVEL

Uncertain

0.52

Sift

Benign

0.098

T;T

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.85

MutPred

0.94

Gain of glycosylation at N3175 (P = 0.0206);Gain of glycosylation at N3175 (P = 0.0206);

MVP

0.97

MPC

0.35

ClinPred

0.99

GERP RS

5.8

Varity_R

0.25

gMVP

0.77

Splicing

Name

Calibrated prediction

Score

Prediction

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over