rs5030828

Positions:

• chr3-10142101-T-A
• chr3-10142101-T-C

Variant summary

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

The NM_000551.4(VHL):​c.254T>A​(p.Leu85Gln) 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. L85V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: VHL NM_000551.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.790

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 3 benign, 12 uncertain in NM_000551.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-10142099-GCTG-GTTT is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VHL	NM_000551.4	c.254T>A	p.Leu85Gln	missense_variant	1/3	ENST00000256474.3
VHL	NM_001354723.2	c.254T>A	p.Leu85Gln	missense_variant	1/3
VHL	NM_198156.3	c.254T>A	p.Leu85Gln	missense_variant	1/2
VHL	NR_176335.1	n.324T>A		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VHL	ENST00000256474.3	c.254T>A	p.Leu85Gln	missense_variant	1/3	1	NM_000551.4	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	0.14
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	18
DANN	Benign	0.94
DEOGEN2	Uncertain	0.64	D;.
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.064
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.83	T;T
M_CAP	Pathogenic	1.0	D
MetaRNN	Uncertain	0.72	D;D
MetaSVM	Pathogenic	1.2	D
MutationAssessor	Benign	0.26	N;N
MutationTaster	Benign	0.98	N;N
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.060	N;N
REVEL	Uncertain	0.52
Sift4G	Benign	0.43	T;T
Polyphen		0.95	P;P
Vest4		0.18
MutPred		0.80		Gain of disorder (P = 0.0254);Gain of disorder (P = 0.0254);
MVP		1.0
MPC		0.43
ClinPred		0.34	T
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.58
gMVP		0.91

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: chr3-10183785;