rs786201604

Positions:

• chr3-10142122-A-G
• chr3-10142122-A-T
• chr3-10142122-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000551.4(VHL):​c.275A>G​(p.Asp92Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: VHL NM_000551.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.01

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a chain von Hippel-Lindau disease tumor suppressor (size 212) in uniprot entity VHL_HUMAN there are 96 pathogenic changes around while only 8 benign (92%) in NM_000551.4
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VHL	NM_000551.4	c.275A>G	p.Asp92Gly	missense_variant	1/3	ENST00000256474.3	NP_000542.1
VHL	NM_001354723.2	c.275A>G	p.Asp92Gly	missense_variant	1/3		NP_001341652.1
VHL	NM_198156.3	c.275A>G	p.Asp92Gly	missense_variant	1/2		NP_937799.1
VHL	NR_176335.1	n.345A>G		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VHL	ENST00000256474.3	c.275A>G	p.Asp92Gly	missense_variant	1/3	1	NM_000551.4	ENSP00000256474	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.90	D;.
Eigen	Benign	-0.11
Eigen_PC	Benign	0.016
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.72	T;T
M_CAP	Pathogenic	0.99	D
MetaRNN	Uncertain	0.65	D;D
MetaSVM	Pathogenic	1.2	D
MutationAssessor	Benign	0.34	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Uncertain	0.64
Sift	Benign	0.065	.;T
Sift4G	Benign	0.36	T;T
Polyphen		0.18	B;P
Vest4		0.29
MutPred		0.59		Loss of stability (P = 0.069);Loss of stability (P = 0.069);
MVP		1.0
MPC		0.52
ClinPred		0.66	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.76
gMVP		0.90

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-10183806; COSMIC: COSV56555732; COSMIC: COSV56555732;