3-10146744-T-G

Variant names:

• chr3-10146744-T-G
• rs1678607
• NM_000551.4:c.463+108T>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 19 publications found

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 Gene-Disease associations (from GenCC):

• pheochromocytoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• von Hippel-Lindau disease

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• renal cell carcinoma

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• autosomal recessive secondary polycythemia not associated with VHL gene

  Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics
• Chuvash polycythemia

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 1292423.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.928 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000551.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VHL	NM_000551.4	MANE Select	c.463+108T>G		intron	N/A	NP_000542.1
	VHL	NM_001354723.2		c.*18-3043T>G		intron	N/A	NP_001341652.1
	VHL	NM_198156.3		c.341-3043T>G		intron	N/A	NP_937799.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VHL	ENST00000256474.3	TSL:1 MANE Select	c.463+108T>G		intron	N/A	ENSP00000256474.3
	VHL	ENST00000345392.3	TSL:1	c.341-3043T>G		intron	N/A	ENSP00000344757.2
	VHL	ENST00000477538.2	TSL:1	n.1343+108T>G		intron	N/A

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

African (AFR) AF: 0.937 AC: 26685 AN: 28478

American (AMR) AF: 0.862 AC: 37653 AN: 43676

Ashkenazi Jewish (ASJ) AF: 0.925 AC: 22401 AN: 24206

East Asian (EAS) AF: 0.833 AC: 31735 AN: 38080

South Asian (SAS) AF: 0.789 AC: 63677 AN: 80748

European-Finnish (FIN) AF: 0.900 AC: 43969 AN: 48832

Middle Eastern (MID) AF: 0.830 AC: 4319 AN: 5206

European-Non Finnish (NFE) AF: 0.875 AC: 787186 AN: 899282

Other (OTH) AF: 0.874 AC: 45284 AN: 51810

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

African (AFR) AF: 0.936 AC: 38870 AN: 41522

American (AMR) AF: 0.869 AC: 13294 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.928 AC: 3218 AN: 3468

East Asian (EAS) AF: 0.885 AC: 4582 AN: 5176

South Asian (SAS) AF: 0.791 AC: 3812 AN: 4818

European-Finnish (FIN) AF: 0.902 AC: 9560 AN: 10598

Middle Eastern (MID) AF: 0.844 AC: 248 AN: 294

European-Non Finnish (NFE) AF: 0.875 AC: 59505 AN: 68014

Other (OTH) AF: 0.876 AC: 1850 AN: 2112

Alfa AF: 0.880 Hom.: 86497

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

Jun 22, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.3
DANN	Benign	0.46
PhyloP100		-0.59
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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