chr3-10146578-A-T

Variant names:

• chr3-10146578-A-T
• rs119103278
• NM_000551.4:c.405A>T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PS1 PM1 PM2 PP3

The NM_000551.4(VHL):​c.405A>T​(p.Leu135Phe) 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 pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Synonymous variant affecting the same amino acid position (i.e. L135L) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: VHL NM_000551.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0260
• Publications: 0 publications found

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]

VHL Gene-Disease associations (from GenCC):

• pheochromocytoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• von Hippel-Lindau disease

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• renal cell carcinoma

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• autosomal recessive secondary polycythemia not associated with VHL gene

  Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics
• Chuvash polycythemia

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PS1: Transcript NM_000551.4 (VHL) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 2221
• PM1: In a hotspot region, there are 10 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.762

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VHL	NM_000551.4	c.405A>T	p.Leu135Phe	missense_variant	Exon 2 of 3	ENST00000256474.3	NP_000542.1
VHL	NR_176335.1	n.734A>T		non_coding_transcript_exon_variant	Exon 3 of 4
VHL	NM_001354723.2	c.*18-3209A>T		intron_variant	Intron 2 of 2		NP_001341652.1
VHL	NM_198156.3	c.341-3209A>T		intron_variant	Intron 1 of 1		NP_937799.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VHL	ENST00000256474.3	c.405A>T	p.Leu135Phe	missense_variant	Exon 2 of 3	1	NM_000551.4	ENSP00000256474.3

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	Pathogenic	0.63
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.68	T
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Uncertain	0.74	D
MutationAssessor	Benign	1.8	L
PhyloP100		-0.026
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.49
Sift4G	Uncertain	0.017	D
Polyphen		0.84	P
Vest4		0.53
MutPred		0.70		Gain of sheet (P = 0.0344);
MVP		1.0
MPC		1.1
ClinPred		0.92	D
GERP RS		-3.0
Varity_R		0.73
gMVP		0.88
Mutation Taster		=17/83	disease causing

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

Other links and lift over

dbSNP: rs119103278; hg19: chr3-10188262; COSMIC: COSV56564185;