3-10142192-G-C

Variant names:

• chr3-10142192-G-C
• rs61758376
• NM_000551.4:c.340+5G>C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_000551.4(VHL):​c.340+5G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00454 in 1,596,998 control chromosomes in the GnomAD database, including 206 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0040 (16 hom., cov: 33)
  • Exomes 𝑓: 0.0046 (190 hom.)
• Consequence: VHL NM_000551.4 splice_region, intron
• Scores: Splicing: ADA: 0.9553
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:24
• Conservation: PhyloP100: 2.43
• Publications: 16 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: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, Genomics England PanelApp, G2P
• 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.24).
• BP6: Variant 3-10142192-G-C is Benign according to our data. Variant chr3-10142192-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 36901.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0524 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VHL	NM_000551.4	MANE Select	c.340+5G>C		splice_region intron	N/A	NP_000542.1	A0A024R2F2
	VHL	NM_001354723.2		c.340+5G>C		splice_region intron	N/A	NP_001341652.1	A0A8Q3WL21
	VHL	NM_198156.3		c.340+5G>C		splice_region intron	N/A	NP_937799.1	A0A0S2Z4K1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VHL	ENST00000256474.3	TSL:1 MANE Select	c.340+5G>C		splice_region intron	N/A	ENSP00000256474.3	P40337-1
	VHL	ENST00000345392.3	TSL:1	c.340+5G>C		splice_region intron	N/A	ENSP00000344757.2	P40337-2
	VHL	ENST00000477538.2	TSL:1	n.391G>C		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes AF: 0.00401 AC: 610 AN: 152178 Hom.: 15 Cov.: 33

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00923

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0250

Gnomad SAS AF: 0.0585

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.0125 AC: 2715 AN: 217310 AF XY: 0.0138

Gnomad AFR exome AF: 0.000390

Gnomad AMR exome AF: 0.0206

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0254

Gnomad FIN exome AF: 0.000270

Gnomad NFE exome AF: 0.000481

Gnomad OTH exome AF: 0.00669

GnomAD4 exome AF: 0.00460 AC: 6648 AN: 1444702 Hom.: 190 Cov.: 32 AF XY: 0.00583 AC XY: 4191 AN XY: 718988

African (AFR) AF: 0.000269 AC: 9 AN: 33434

American (AMR) AF: 0.0197 AC: 876 AN: 44500

Ashkenazi Jewish (ASJ) AF: 0.0000768 AC: 2 AN: 26044

East Asian (EAS) AF: 0.0201 AC: 795 AN: 39626

South Asian (SAS) AF: 0.0496 AC: 4259 AN: 85788

European-Finnish (FIN) AF: 0.000261 AC: 10 AN: 38346

Middle Eastern (MID) AF: 0.00489 AC: 28 AN: 5724

European-Non Finnish (NFE) AF: 0.000268 AC: 298 AN: 1111088

Other (OTH) AF: 0.00617 AC: 371 AN: 60152

GnomAD4 genome AF: 0.00400 AC: 609 AN: 152296 Hom.: 16 Cov.: 33 AF XY: 0.00516 AC XY: 384 AN XY: 74472

African (AFR) AF: 0.000529 AC: 22 AN: 41566

American (AMR) AF: 0.00942 AC: 144 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0249 AC: 129 AN: 5180

South Asian (SAS) AF: 0.0579 AC: 280 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000368 AC: 25 AN: 68016

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.000856 Hom.: 1

Bravo AF: 0.00371

Asia WGS AF: 0.0270 AC: 95 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	7	Von Hippel-Lindau syndrome (7)
-	-	6	not provided (6)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	1	Tuberous sclerosis 2 (1)
-	-	1	Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.24
CADD	Benign	16
DANN	Benign	0.95
PhyloP100		2.4
PromoterAI		-0.24	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.96
dbscSNV1_RF	Benign	0.67
SpliceAI score (max)		0.040		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: rs61758376; hg19: chr3-10183876; COSMIC: COSV104558389;