rs372757722

chr3-10146600-G-Achr3-10146600-G-C

Variant summary

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

The NM_000551.4(VHL):c.427G>A(p.Asp143Asn) 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. D143H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: VHL NM_000551.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.69

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 hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 uncertain in NM_000551.4
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VHL	NM_000551.4	c.427G>A	p.Asp143Asn	missense_variant	2/3	ENST00000256474.3
VHL	NM_001354723.2	c.*18-3187G>A		intron_variant
VHL	NM_198156.3	c.341-3187G>A		intron_variant
VHL	NR_176335.1	n.756G>A		non_coding_transcript_exon_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VHL	ENST00000256474.3	c.427G>A	p.Asp143Asn	missense_variant	2/3	1	NM_000551.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	0.0024	T
BayesDel_noAF	Benign	-0.23
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.59	D
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.74	T
M_CAP	Pathogenic	0.62	D
MetaRNN	Uncertain	0.47	T
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Benign	-1.7	N
MutationTaster	Benign	1.0	D;N
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	0.22	N
REVEL	Uncertain	0.29
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.43
MutPred		0.65		Gain of sheet (P = 0.0344);
MVP		0.98
MPC		0.32
ClinPred		0.98	D
GERP RS		2.9
Varity_R		0.32
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: chr3-10188284; COSMIC: COSV99847308;