X-47566722-C-G

Position:

• chrX-47566722-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM5 PP5

The NM_001654.5(ARAF):​c.641C>G​(p.Ser214Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S214A) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: ARAF NM_001654.5 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:3 O:1
• Conservation: PhyloP100: 7.64

Genes affected

ARAF (HGNC:646): (A-Raf proto-oncogene, serine/threonine kinase) Enables protein serine/threonine kinase activity. Involved in negative regulation of apoptotic process; regulation of TOR signaling; and regulation of cellular protein metabolic process. Predicted to be active in cytosol and mitochondrion. Biomarker of high grade glioma. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-47566721-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376367.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP5: Variant X-47566722-C-G is Pathogenic according to our data. Variant chrX-47566722-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376137.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARAF	NM_001654.5	c.641C>G	p.Ser214Cys	missense_variant	7/16	ENST00000377045.9
ARAF	NM_001256196.2	c.650C>G	p.Ser217Cys	missense_variant	7/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARAF	ENST00000377045.9	c.641C>G	p.Ser214Cys	missense_variant	7/16	1	NM_001654.5	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Papillary renal cell carcinoma, sporadic Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Lung adenocarcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Malignant melanoma of skin Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Non-small cell lung carcinoma Other:1

not provided, no classification provided

literature only

Database of Curated Mutations (DoCM)

Mar 10, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.48	T;D
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Uncertain	0.59	D;D
MetaSVM	Uncertain	0.34	D
MutationAssessor	Uncertain	2.7	.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.8	.;D
REVEL	Uncertain	0.64
Sift	Pathogenic	0.0	.;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		0.99	.;D
Vest4		0.53
MutPred		0.30		.;Loss of glycosylation at S214 (P = 0.0279);
MVP		0.84
MPC		0.33
ClinPred		0.99	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.80
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1057519786; hg19: chrX-47426121; COSMIC: COSV51695114; COSMIC: COSV51695114;