rs1060503557

Variant names:

• chr3-10141848-A-G
• rs1060503557
• NM_000551.4:c.1A>G

Your query was ambiguous. Multiple possible variants found:

• chr3-10141848-A-G
• chr3-10141848-A-T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_000551.4(VHL):​c.1A>G​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000723 in 1,383,702 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: VHL NM_000551.4 start_lost
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:4
• Conservation: PhyloP100: -0.139
• Publications: 5 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 7 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 5 pathogenic variants. Next in-frame start position is after 54 codons. Genomic position: 10142007. Lost 0.249 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-10141848-A-G is Pathogenic according to our data. Variant chr3-10141848-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 548790.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000551.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VHL	NM_000551.4	MANE Select	c.1A>G	p.Met1?	start_lost	Exon 1 of 3	NP_000542.1
	VHL	NM_001354723.2		c.1A>G	p.Met1?	start_lost	Exon 1 of 3	NP_001341652.1
	VHL	NM_198156.3		c.1A>G	p.Met1?	start_lost	Exon 1 of 2	NP_937799.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VHL	ENST00000256474.3	TSL:1 MANE Select	c.1A>G	p.Met1?	start_lost	Exon 1 of 3	ENSP00000256474.3
	VHL	ENST00000345392.3	TSL:1	c.1A>G	p.Met1?	start_lost	Exon 1 of 2	ENSP00000344757.2
	VHL	ENST00000477538.2	TSL:1	n.47A>G		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.23e-7 AC: 1 AN: 1383702 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 681222

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30822

American (AMR) AF: 0.00 AC: 0 AN: 33696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24498

East Asian (EAS) AF: 0.00 AC: 0 AN: 35338

South Asian (SAS) AF: 0.00 AC: 0 AN: 77990

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47884

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4020

European-Non Finnish (NFE) AF: 9.33e-7 AC: 1 AN: 1072328

Other (OTH) AF: 0.00 AC: 0 AN: 57126

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	1	-	not provided (2)
-	1	-	Hereditary cancer-predisposing syndrome (1)
-	1	-	Von Hippel-Lindau syndrome (1)
-	1	-	Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.038	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	9.4
DANN	Benign	0.66
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.31	N
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Benign	-0.51	T
PhyloP100		-0.14
PROVEAN	Benign	-0.39	N
REVEL	Uncertain	0.34
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.060	T
Polyphen		0.0	B
Vest4		0.23
MutPred		0.99		Gain of MoRF binding (P = 0.2114)
MVP		0.85
ClinPred		0.74	D
GERP RS		0.76
PromoterAI		-0.081	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.37
gMVP		0.54
Mutation Taster		=102/98	polymorphism

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: rs1060503557; hg19: chr3-10183532; COSMIC: COSV56555214;