3-10149827-C-G

Position:

• chr3-10149827-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The ENST00000256474.3(VHL):​c.504C>G​(p.Ser168Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S168N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: VHL ENST00000256474.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.444

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in ENST00000256474.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-10149824-GAG-GTTGTCCGT is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VHL	NM_000551.4	c.504C>G	p.Ser168Arg	missense_variant	3/3	ENST00000256474.3	NP_000542.1
VHL	NM_198156.3	c.381C>G	p.Ser127Arg	missense_variant	2/2		NP_937799.1
VHL	NM_001354723.2	c.*58C>G		3_prime_UTR_variant	3/3		NP_001341652.1
VHL	NR_176335.1	n.833C>G		non_coding_transcript_exon_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VHL	ENST00000256474.3	c.504C>G	p.Ser168Arg	missense_variant	3/3	1	NM_000551.4	ENSP00000256474	P1

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	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D;.
Eigen	Benign	-0.049
Eigen_PC	Benign	-0.054
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.81	T;T
M_CAP	Pathogenic	0.68	D
MetaRNN	Uncertain	0.65	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	0.68	N;.
MutationTaster	Benign	0.84	D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.90	N;N
REVEL	Uncertain	0.63
Sift	Benign	0.16	.;T
Sift4G	Benign	0.28	T;T
Polyphen		1.0	D;D
Vest4		0.17
MutPred		0.72		Gain of MoRF binding (P = 0.0142);.;
MVP		1.0
MPC		1.0
ClinPred		0.71	D
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.63
gMVP		0.74

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: chr3-10191511;