chr3-10146744-T-G

Position:

• chr3-10146744-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000551.4(VHL):​c.463+108T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.873 in 1,372,520 control chromosomes in the GnomAD database, including 524,322 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.89 (60680 hom., cov: 32)
  • Exomes 𝑓: 0.87 (463642 hom.)
• Consequence: VHL NM_000551.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.586

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 3-10146744-T-G is Benign according to our data. Variant chr3-10146744-T-G is described in ClinVar as [Benign]. Clinvar id is 1292423.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10146744-T-G is described in Lovd as [Benign].
• 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	Protein	UniProt
VHL	NM_000551.4	c.463+108T>G		intron_variant		ENST00000256474.3	NP_000542.1
VHL	NM_001354723.2	c.*18-3043T>G		intron_variant			NP_001341652.1
VHL	NM_198156.3	c.341-3043T>G		intron_variant			NP_937799.1
VHL	NR_176335.1	n.792+108T>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VHL	ENST00000256474.3	c.463+108T>G		intron_variant		1	NM_000551.4	ENSP00000256474.3

Frequencies

GnomAD3 genomes AF: 0.892 AC: 135655 AN: 152084 Hom.: 60644 Cov.: 32

Gnomad AFR AF: 0.936

Gnomad AMI AF: 0.881

Gnomad AMR AF: 0.869

Gnomad ASJ AF: 0.928

Gnomad EAS AF: 0.886

Gnomad SAS AF: 0.792

Gnomad FIN AF: 0.902

Gnomad MID AF: 0.842

Gnomad NFE AF: 0.875

Gnomad OTH AF: 0.884

GnomAD4 exome AF: 0.871 AC: 1062909 AN: 1220318 Hom.: 463642 AF XY: 0.868 AC XY: 536797 AN XY: 618220

Gnomad4 AFR exome AF: 0.937

Gnomad4 AMR exome AF: 0.862

Gnomad4 ASJ exome AF: 0.925

Gnomad4 EAS exome AF: 0.833

Gnomad4 SAS exome AF: 0.789

Gnomad4 FIN exome AF: 0.900

Gnomad4 NFE exome AF: 0.875

Gnomad4 OTH exome AF: 0.874

GnomAD4 genome AF: 0.892 AC: 135741 AN: 152202 Hom.: 60680 Cov.: 32 AF XY: 0.893 AC XY: 66442 AN XY: 74414

Gnomad4 AFR AF: 0.936

Gnomad4 AMR AF: 0.869

Gnomad4 ASJ AF: 0.928

Gnomad4 EAS AF: 0.885

Gnomad4 SAS AF: 0.791

Gnomad4 FIN AF: 0.902

Gnomad4 NFE AF: 0.875

Gnomad4 OTH AF: 0.876

Alfa AF: 0.888 Hom.: 10536

Bravo AF: 0.894

Asia WGS AF: 0.824 AC: 2866 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.3
DANN	Benign	0.46

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: rs1678607; hg19: chr3-10188428; COSMIC: COSV56555019;