rs3087631

chr16-2089126-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001009944.3(PKD1):c.*601T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.276 in 169,558 control chromosomes in the GnomAD database, including 9,495 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.29 (9233 hom., cov: 34)
  • Exomes 𝑓: 0.15 (262 hom.)
• Consequence: PKD1 NM_001009944.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0540

Genes affected

TSC2 (HGNC:12363): (TSC complex subunit 2) This gene is a tumor suppressor gene that encodes the growth inhibitory protein tuberin. Tuberin interacts with hamartin to form the TSC protein complex which functions in the control of cell growth. This TSC protein complex negatively regulates mammalian target of rapamycin complex 1 (mTORC1) signaling which is a major regulator of anabolic cell growth. Mutations in this gene have been associated with tuberous sclerosis and lymphangioleiomyomatosis. [provided by RefSeq, May 2022]

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.581 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC2	NM_000548.5	c.*516A>T		3_prime_UTR_variant	42/42	ENST00000219476.9
PKD1	NM_001009944.3	c.*601T>A		3_prime_UTR_variant	46/46	ENST00000262304.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC2	ENST00000219476.9	c.*516A>T		3_prime_UTR_variant	42/42	5	NM_000548.5
PKD1	ENST00000262304.9	c.*601T>A		3_prime_UTR_variant	46/46	1	NM_001009944.3	P5

Frequencies

GnomAD3 genomes AF: 0.290 AC: 44125 AN: 152020 Hom.: 9199 Cov.: 34

Gnomad AFR AF: 0.587

Gnomad AMI AF: 0.134

Gnomad AMR AF: 0.207

Gnomad ASJ AF: 0.252

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0937

Gnomad FIN AF: 0.232

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.179

Gnomad OTH AF: 0.258

GnomAD4 exome AF: 0.153 AC: 2665 AN: 17420 Hom.: 262 Cov.: 0 AF XY: 0.154 AC XY: 1374 AN XY: 8926

Gnomad4 AFR exome AF: 0.513

Gnomad4 AMR exome AF: 0.150

Gnomad4 ASJ exome AF: 0.202

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0917

Gnomad4 FIN exome AF: 0.180

Gnomad4 NFE exome AF: 0.162

Gnomad4 OTH exome AF: 0.195

GnomAD4 genome AF: 0.291 AC: 44213 AN: 152138 Hom.: 9233 Cov.: 34 AF XY: 0.287 AC XY: 21332 AN XY: 74368

Gnomad4 AFR AF: 0.587

Gnomad4 AMR AF: 0.207

Gnomad4 ASJ AF: 0.252

Gnomad4 EAS AF: 0.00135

Gnomad4 SAS AF: 0.0934

Gnomad4 FIN AF: 0.232

Gnomad4 NFE AF: 0.179

Gnomad4 OTH AF: 0.255

Alfa AF: 0.239 Hom.: 844

Bravo AF: 0.303

Asia WGS AF: 0.0840 AC: 293 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	5.3
Dann	Benign	0.56
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Other links and lift over

dbSNP: rs3087631; hg19: chr16-2139127; COSMIC: COSV51913315; COSMIC: COSV51913315;