NM_000551.4:c.53C>T

Variant names:

• chr3-10141900-C-T
• rs1553619302
• NM_000551.4:c.53C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_000551.4(VHL):​c.53C>T​(p.Ala18Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000362 in 1,379,818 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. A18G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: VHL NM_000551.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: -0.344
• Publications: 0 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.049024343).
• BP6: Variant 3-10141900-C-T is Benign according to our data. Variant chr3-10141900-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 456591.

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.53C>T	p.Ala18Val	missense	Exon 1 of 3	NP_000542.1
	VHL	NM_001354723.2		c.53C>T	p.Ala18Val	missense	Exon 1 of 3	NP_001341652.1
	VHL	NM_198156.3		c.53C>T	p.Ala18Val	missense	Exon 1 of 2	NP_937799.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VHL	ENST00000256474.3	TSL:1 MANE Select	c.53C>T	p.Ala18Val	missense	Exon 1 of 3	ENSP00000256474.3
	VHL	ENST00000345392.3	TSL:1	c.53C>T	p.Ala18Val	missense	Exon 1 of 2	ENSP00000344757.2
	VHL	ENST00000477538.2	TSL:1	n.99C>T		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000362 AC: 5 AN: 1379818 Hom.: 0 Cov.: 32 AF XY: 0.00000295 AC XY: 2 AN XY: 678110

African (AFR) AF: 0.00 AC: 0 AN: 30788

American (AMR) AF: 0.00 AC: 0 AN: 33948

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24332

East Asian (EAS) AF: 0.0000283 AC: 1 AN: 35280

South Asian (SAS) AF: 0.00 AC: 0 AN: 77302

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48030

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4052

European-Non Finnish (NFE) AF: 0.00000374 AC: 4 AN: 1069202

Other (OTH) AF: 0.00 AC: 0 AN: 56884

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	1	-	not provided (1)
-	1	-	Von Hippel-Lindau syndrome (1)
-	1	-	Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	11
DANN	Benign	0.92
DEOGEN2	Benign	0.30	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.049	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	-0.34	N
PhyloP100		-0.34
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.32	N
REVEL	Benign	0.17
Sift	Benign	0.54	T
Sift4G	Benign	0.41	T
Polyphen		0.0	B
Vest4		0.043
MutPred		0.24		Gain of glycosylation at Y23 (P = 0.0012)
MVP		0.95
MPC		0.63
ClinPred		0.12	T
GERP RS		-0.19
PromoterAI		-0.0070	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.058
gMVP		0.34
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1553619302; hg19: chr3-10183584;