3-10153488-T-G

Position:

• chr3-10153488-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_000551.4(VHL):​c.*3523T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0202 in 152,210 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.020 (49 hom., cov: 32)
• Consequence: VHL NM_000551.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.208

Genes affected

VHL (HGNC:12687): (von Hippel-Lindau tumor suppressor) This gene encodes a component of a ubiquitination complex. The encoded protein is involved in the ubiquitination and degradation of hypoxia-inducible-factor (HIF), which is a transcription factor that plays a central role in the regulation of gene expression by oxygen. In addition to oxygen-related gene expression, this protein plays a role in many other cellular processes including cilia formation, cytokine signaling, regulation of senescence, and formation of the extracellular matrix. Variants of this gene are associated with von Hippel-Lindau syndrome, pheochromocytoma, erythrocytosis, renal cell carcinoma, and cerebellar hemangioblastoma. [provided by RefSeq, Jun 2022]

VHL (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 3-10153488-T-G is Benign according to our data. Variant chr3-10153488-T-G is described in ClinVar as [Benign]. Clinvar id is 342507.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0202 (3070/152210) while in subpopulation AMR AF= 0.0349 (534/15280). AF 95% confidence interval is 0.0325. There are 49 homozygotes in gnomad4. There are 1484 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 49 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VHL	NM_000551.4	c.*3523T>G		3_prime_UTR_variant	3/3	ENST00000256474.3	NP_000542.1
VHL	NM_001354723.2	c.*3719T>G		3_prime_UTR_variant	3/3		NP_001341652.1
VHL	NM_198156.3	c.*3523T>G		3_prime_UTR_variant	2/2		NP_937799.1
VHL	NR_176335.1	n.4494T>G		non_coding_transcript_exon_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VHL	ENST00000256474.3	c.*3523T>G		3_prime_UTR_variant	3/3	1	NM_000551.4	ENSP00000256474.3
VHL	ENST00000696153.1	c.*3523T>G		3_prime_UTR_variant	4/4			ENSP00000512444.1

Frequencies

GnomAD3 genomes AF: 0.0202 AC: 3073 AN: 152090 Hom.: 50 Cov.: 32

Gnomad AFR AF: 0.00548

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0351

Gnomad ASJ AF: 0.0144

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00518

Gnomad FIN AF: 0.0404

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0259

Gnomad OTH AF: 0.0182

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0202 AC: 3070 AN: 152210 Hom.: 49 Cov.: 32 AF XY: 0.0199 AC XY: 1484 AN XY: 74438

Gnomad4 AFR AF: 0.00547

Gnomad4 AMR AF: 0.0349

Gnomad4 ASJ AF: 0.0144

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00539

Gnomad4 FIN AF: 0.0404

Gnomad4 NFE AF: 0.0259

Gnomad4 OTH AF: 0.0180

Alfa AF: 0.0228 Hom.: 7

Bravo AF: 0.0203

Asia WGS AF: 0.00751 AC: 26 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Von Hippel-Lindau syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	3.1
DANN	Benign	0.77

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs17610448; hg19: chr3-10195172;