3-10141878-G-C

Variant names:

• chr3-10141878-G-C
• rs1236604706
• NM_000551.4:c.31G>C

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_000551.4(VHL):​c.31G>C​(p.Ala11Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000029 in 1,381,562 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A11S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: VHL NM_000551.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 1.18
• Publications: 2 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: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17289764).
• BP6: Variant 3-10141878-G-C is Benign according to our data. Variant chr3-10141878-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 456583.

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.31G>C	p.Ala11Pro	missense	Exon 1 of 3	NP_000542.1	A0A024R2F2
	VHL	NM_001354723.2		c.31G>C	p.Ala11Pro	missense	Exon 1 of 3	NP_001341652.1	A0A8Q3WL21
	VHL	NM_198156.3		c.31G>C	p.Ala11Pro	missense	Exon 1 of 2	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.31G>C	p.Ala11Pro	missense	Exon 1 of 3	ENSP00000256474.3	P40337-1
	VHL	ENST00000345392.3	TSL:1	c.31G>C	p.Ala11Pro	missense	Exon 1 of 2	ENSP00000344757.2	P40337-2
	VHL	ENST00000477538.2	TSL:1	n.77G>C		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000213 AC: 3 AN: 140792 AF XY: 0.0000134

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000277

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000290 AC: 4 AN: 1381562 Hom.: 0 Cov.: 32 AF XY: 0.00000147 AC XY: 1 AN XY: 679256

African (AFR) AF: 0.00 AC: 0 AN: 30866

American (AMR) AF: 0.00 AC: 0 AN: 34100

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24436

East Asian (EAS) AF: 0.000113 AC: 4 AN: 35332

South Asian (SAS) AF: 0.00 AC: 0 AN: 77584

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48056

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4014

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1070180

Other (OTH) AF: 0.00 AC: 0 AN: 56994

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Von Hippel-Lindau syndrome (1)
-	1	-	Von Hippel-Lindau syndrome;C0031511:Pheochromocytoma;C1837915:Chuvash polycythemia;CN074294:Nonpapillary renal cell carcinoma (1)
-	1	-	Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	20
DANN	Benign	0.94
DEOGEN2	Benign	0.38	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.56	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	0.69	N
PhyloP100		1.2
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.48	N
REVEL	Uncertain	0.32
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.096	T
Polyphen		0.97	D
Vest4		0.16
MutPred		0.40		Gain of loop (P = 0.0013)
MVP		0.96
MPC		0.93
ClinPred		0.40	T
GERP RS		1.6
PromoterAI		-0.15	Neutral
Varity_R		0.30
gMVP		0.48
Mutation Taster		=96/4	polymorphism

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: rs1236604706; hg19: chr3-10183562;