3-10145330-A-G

Variant summary

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

The NM_000551.4(VHL):c.341-1184A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.892 in 152,240 control chromosomes in the GnomAD database, including 60,696 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 0.89 (60696 hom., cov: 33)
• Consequence: VHL NM_000551.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.259

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.928 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VHL	NM_000551.4	c.341-1184A>G		intron_variant		ENST00000256474.3
VHL	NM_001354723.2	c.*17+2309A>G		intron_variant
VHL	NM_198156.3	c.340+3143A>G		intron_variant
VHL	NR_176335.1	n.670-1184A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VHL	ENST00000256474.3	c.341-1184A>G		intron_variant		1	NM_000551.4	P1

Frequencies

GnomAD3 genomes AF: 0.892 AC: 135697 AN: 152122 Hom.: 60660 Cov.: 33

Gnomad AFR AF: 0.936

Gnomad AMI AF: 0.881

Gnomad AMR AF: 0.870

Gnomad ASJ AF: 0.928

Gnomad EAS AF: 0.885

Gnomad SAS AF: 0.791

Gnomad FIN AF: 0.902

Gnomad MID AF: 0.842

Gnomad NFE AF: 0.875

Gnomad OTH AF: 0.883

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

GnomAD4 genome AF: 0.892 AC: 135783 AN: 152240 Hom.: 60696 Cov.: 33 AF XY: 0.893 AC XY: 66447 AN XY: 74412

Gnomad4 AFR AF: 0.936

Gnomad4 AMR AF: 0.870

Gnomad4 ASJ AF: 0.928

Gnomad4 EAS AF: 0.885

Gnomad4 SAS AF: 0.790

Gnomad4 FIN AF: 0.902

Gnomad4 NFE AF: 0.875

Gnomad4 OTH AF: 0.876

Alfa AF: 0.878 Hom.: 4862

Bravo AF: 0.894

Asia WGS AF: 0.824 AC: 2867 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
Cadd	Benign	9.1
Dann	Benign	0.91

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: rs779812; hg19: chr3-10187014;