chrX-47567066-C-T

Variant names:

• chrX-47567066-C-T
• rs923151586
• NM_001654.5:c.808C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001654.5(ARAF):​c.808C>T​(p.Pro270Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000891 in 112,295 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000089 (0 hom., 1 hem., cov: 23)
• Consequence: ARAF NM_001654.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.41

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18541425).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARAF	NM_001654.5	c.808C>T	p.Pro270Ser	missense_variant	Exon 9 of 16	ENST00000377045.9	NP_001645.1
ARAF	NM_001256196.2	c.817C>T	p.Pro273Ser	missense_variant	Exon 9 of 16		NP_001243125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARAF	ENST00000377045.9	c.808C>T	p.Pro270Ser	missense_variant	Exon 9 of 16	1	NM_001654.5	ENSP00000366244.4

Frequencies

GnomAD3 genomes AF: 0.00000891 AC: 1 AN: 112295 Hom.: 0 Cov.: 23 AF XY: 0.0000290 AC XY: 1 AN XY: 34435

Gnomad AFR AF: 0.0000324

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000891 AC: 1 AN: 112295 Hom.: 0 Cov.: 23 AF XY: 0.0000290 AC XY: 1 AN XY: 34435

Gnomad4 AFR AF: 0.0000324

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T;T
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.80	T;T
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.19	T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.64	.;N
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.51	.;N
REVEL	Benign	0.15
Sift	Benign	0.23	.;T
Sift4G	Benign	0.58	T;T
Polyphen		0.024	.;B
Vest4		0.25
MutPred		0.23		.;Gain of phosphorylation at P270 (P = 6e-04);
MVP		0.67
MPC		0.079
ClinPred		0.31	T
GERP RS		3.9
Varity_R		0.13
gMVP		0.53

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

LitVar

Other links and lift over

dbSNP: rs923151586; hg19: chrX-47426465;