rs1060503549

Variant names:

• chr3-10149943-C-A
• NM_000551.4:c.620C>A

Your query was ambiguous. Multiple possible variants found:

• chr3-10149943-C-A
• chr3-10149943-C-G
• chr3-10149943-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1 PM2 BP4_Strong

The NM_000551.4(VHL):​c.620C>A​(p.Ala207Glu) 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. 12/21 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: 0.799

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 0 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=0.062283456).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VHL	NM_000551.4	c.620C>A	p.Ala207Glu	missense_variant	Exon 3 of 3	ENST00000256474.3	NP_000542.1
VHL	NM_198156.3	c.497C>A	p.Ala166Glu	missense_variant	Exon 2 of 2		NP_937799.1
VHL	NM_001354723.2	c.*174C>A		3_prime_UTR_variant	Exon 3 of 3		NP_001341652.1
VHL	NR_176335.1	n.949C>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.620C>A	p.Ala207Glu	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	0.072
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	1.8
DANN	Benign	0.23
DEOGEN2	Benign	0.28	T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.57	T;T
M_CAP	Uncertain	0.089	D
MetaRNN	Benign	0.062	T;T
MetaSVM	Uncertain	0.49	D
MutationAssessor	Benign	-1.2	N;.
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.58	N;N
REVEL	Uncertain	0.44
Sift	Benign	1.0	.;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.045
MutPred		0.58		Gain of glycosylation at T202 (P = 0.025);.;
MVP		0.84
MPC		0.38
ClinPred		0.061	T
GERP RS		-0.58
Varity_R		0.40
gMVP		0.34

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: chr3-10191627;