rs775624944

Variant names:

• chr3-10149962-T-A
• NM_000551.4:c.639T>A

Your query was ambiguous. Multiple possible variants found:

• chr3-10149962-T-A
• chr3-10149962-T-C
• chr3-10149962-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_000551.4(VHL):​c.639T>A​(p.Asp213Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: VHL NM_000551.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.247

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]

ENSG00000287086 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.07786703).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VHL	NM_000551.4	c.639T>A	p.Asp213Glu	missense_variant	Exon 3 of 3	ENST00000256474.3	NP_000542.1
VHL	NM_198156.3	c.516T>A	p.Asp172Glu	missense_variant	Exon 2 of 2		NP_937799.1
VHL	NM_001354723.2	c.*193T>A		3_prime_UTR_variant	Exon 3 of 3		NP_001341652.1
VHL	NR_176335.1	n.968T>A		non_coding_transcript_exon_variant	Exon 4 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VHL	ENST00000256474.3	c.639T>A	p.Asp213Glu	missense_variant	Exon 3 of 3	1	NM_000551.4	ENSP00000256474.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Uncertain	0.099	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	0.42
DANN	Benign	0.83
DEOGEN2	Benign	0.31	T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.37	T;T
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.078	T;T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	0.0	N;.
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.21	N;N
REVEL	Uncertain	0.42
Sift	Benign	0.28	.;T
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.058	B;B
Vest4		0.14
MutPred		0.43		Loss of MoRF binding (P = 0.1567);.;
MVP		0.48
MPC		0.31
ClinPred		0.041	T
GERP RS		-1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.34
gMVP		0.28

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: chr3-10191646;