NM_001009944.3:c.10529C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001009944.3(PKD1):c.10529C>T(p.Thr3510Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0132 in 1,605,754 control chromosomes in the GnomAD database, including 645 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T3510T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.011 ( 45 hom., cov: 33)

Exomes 𝑓: 0.013 ( 600 hom. )

Consequence

PKD1
NM_001009944.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.865

Publications

25 publications found

Variant links:

Genes affected

PKD1 (HGNC:9008): (polycystin 1, transient receptor potential channel interacting) This gene encodes a member of the polycystin protein family. The encoded glycoprotein contains a large N-terminal extracellular region, multiple transmembrane domains and a cytoplasmic C-tail. It is an integral membrane protein that functions as a regulator of calcium permeable cation channels and intracellular calcium homoeostasis. It is also involved in cell-cell/matrix interactions and may modulate G-protein-coupled signal-transduction pathways. It plays a role in renal tubular development, and mutations in this gene cause autosomal dominant polycystic kidney disease type 1 (ADPKD1). ADPKD1 is characterized by the growth of fluid-filled cysts that replace normal renal tissue and result in end-stage renal failure. Splice variants encoding different isoforms have been noted for this gene. Also, six pseudogenes, closely linked in a known duplicated region on chromosome 16p, have been described. [provided by RefSeq, Oct 2008]

PKD1 links:

PKD1-AS1 (HGNC:56035): (PKD1 antisense RNA 1)

PKD1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0022667646).

BP6

Variant 16-2094181-G-A is Benign according to our data. Variant chr16-2094181-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256891.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0959 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3 link	c.10529C>T	p.Thr3510Met	missense_variant	Exon 35 of 46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9 link	c.10529C>T	p.Thr3510Met	missense_variant	Exon 35 of 46	1	NM_001009944.3	ENSP00000262304.4		P98161-1

Frequencies

GnomAD3 genomes

AF:

0.0107

AC:

1621

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00200

Gnomad AMI

AF:

0.0241

Gnomad AMR

AF:

0.00255

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.0575

Gnomad SAS

AF:

0.104

Gnomad FIN

AF:

0.00621

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00855

Gnomad OTH

AF:

0.00766

GnomAD2 exomes

AF:

0.0209

AC:

4944

AN:

236058

AF XY:

0.0248

show subpopulations

Gnomad AFR exome

AF:

0.00197

Gnomad AMR exome

AF:

0.00319

Gnomad ASJ exome

AF:

0.00177

Gnomad EAS exome

AF:

0.0579

Gnomad FIN exome

AF:

0.00694

Gnomad NFE exome

AF:

0.00730

Gnomad OTH exome

AF:

0.0136

GnomAD4 exome

AF:

0.0135

AC:

19585

AN:

1453432

Hom.:

600

Cov.:

AF XY:

0.0160

AC XY:

11534

AN XY:

722754

show subpopulations

African (AFR)

AF:

0.00204

AC:

AN:

33386

American (AMR)

AF:

0.00314

AC:

139

AN:

44308

Ashkenazi Jewish (ASJ)

AF:

0.00185

AC:

AN:

25970

East Asian (EAS)

AF:

0.0521

AC:

2065

AN:

39598

South Asian (SAS)

AF:

0.0944

AC:

8038

AN:

85176

European-Finnish (FIN)

AF:

0.00669

AC:

346

AN:

51694

Middle Eastern (MID)

AF:

0.0116

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.00715

AC:

7921

AN:

1107436

Other (OTH)

AF:

0.0149

AC:

893

AN:

60108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

1051

2101

3152

4202

5253

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

354

708

1062

1416

1770

<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:

0.0106

AC:

1614

AN:

152322

Hom.:

Cov.:

AF XY:

0.0126

AC XY:

938

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.00200

AC:

AN:

41564

American (AMR)

AF:

0.00255

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00259

AC:

AN:

3472

East Asian (EAS)

AF:

0.0575

AC:

298

AN:

5186

South Asian (SAS)

AF:

0.103

AC:

499

AN:

4828

European-Finnish (FIN)

AF:

0.00621

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00856

AC:

582

AN:

68026

Other (OTH)

AF:

0.00758

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

143

215

286

358

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<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:

0.0101

Hom.:

Bravo

AF:

0.00803

TwinsUK

AF:

0.00512

AC:

ALSPAC

AF:

0.00856

AC:

ESP6500AA

AF:

0.00273

AC:

ESP6500EA

AF:

0.00652

AC:

ExAC

AF:

0.0211

AC:

2547

Asia WGS

AF:

0.0500

AC:

175

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 02, 2025

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Polycystic kidney disease, adult type

Benign:2

May 31, 2018

SIB Swiss Institute of Bioinformatics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:curation

This variant is interpreted as a Benign - Stand Alone, for Polycystic kidney disease 1, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: BA1 => Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. -

Feb 03, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Sep 25, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 32823016, 11558899, 11691639, 12007219, 18640754, 19686598, 28578020, 27499327, 26632257, 26722532, 18067079, 20981092, 22185115) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Polycystic kidney disease

Benign:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

The PKD1 p.Thr3510Met variant was identified in 25 of 1248 proband chromosomes (frequency: 0.020) from Japanese, Chinese and Czech individuals or families with ADPKD, and was identified in 6 of 200 control chromosomes from healthy individuals (Mizoguchi 2001, Inoue 2002, Reed 2008, Rossetti 2001, Tsuchiya 2001, Yu 2011, Stekrova 2009). The variant was identified with a co-occurring pathogenic PKD1 variant (Q2142X), increasing the likelihood that the p.Thr3510Met variant does not have clinical significance (Yu 2011). The variant was also identified in dbSNP (ID: rs45478794) â€šÃ„ÃºWith NA alleleâ€šÃ„Ã¹, ADPKD Mutation Database (classification likely neutral), 1000 Genomes Project in 192 of 5013 chromosomes (frequency: 0.0383); HAP-MAP populations: SAS in 120 of 978 chromosomes (frequency: 0.1227)/EAS in 63 of 1008 chromosomes (frequency: 0.0625)/EUR in 8 of 1006 chromosomes (frequency: 0.008), in the NHLBI GO Exome Sequencing Project (ESP) in 56 of 8588 (frequency: 0.0065) European American and in 12 OF 4388 (frequency: 0.0027)African American alleles, and in all populations in the Exome Aggregation Consortium (ExAC) database (released Jan 13, 2015): South Asian in 1466 (87 homozygous) of 130000 chromosomes (frequency: 0.1128), East Asian in 432 (11 homozygous) of 6452 chromosomes (frequency: 0.0067), Other in 15 of 600 chromosomes (frequency: 0.025), European (Non-Finnish) in 388 (2 homozygous) of 45098 chromosomes (frequency: 0.0086), European (Finnish) in 26 of 3626 chromosomes (frequency: 0.0071), Latino in 43 of 7878 chromosomes (frequency: 0.0054) and African in 18 (1 homozygous) of 6646 chromosomes (frequency: 0.0027), increasing the likelihood this could be a low frequency benign variant.The p.Thr3510Met residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 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 dominant polycystic kidney disease

Benign:1

Jan 01, 2019

Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.68

CADD

Benign

6.8

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.23

T;.

Eigen

Benign

-0.70

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.077

LIST_S2

Benign

0.57

T;T

MetaRNN

Benign

0.0023

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.67

N;.

PhyloP100

0.86

PrimateAI

Benign

0.25

PROVEAN

Benign

-1.1

N;N

REVEL

Benign

0.10

Sift

Benign

0.047

D;D

Sift4G

Benign

0.080

T;T

Polyphen

0.86

P;P

Vest4

0.039

ClinPred

0.0025

GERP RS

0.47

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.018

gMVP

0.32

Mutation Taster

=96/4

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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