X-47565277-T-C

Position:

• chrX-47565277-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_001654.5(ARAF):​c.484T>C​(p.Ser162Pro) 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 benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: ARAF NM_001654.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.716

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 2 ACMG points.

• PM1: In a modified_residue Phosphoserine (size 0) in uniprot entity ARAF_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08042613).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARAF	NM_001654.5	c.484T>C	p.Ser162Pro	missense_variant	6/16	ENST00000377045.9
ARAF	NM_001256196.2	c.493T>C	p.Ser165Pro	missense_variant	6/16
ARAF	NM_001256197.2	c.484T>C	p.Ser162Pro	missense_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARAF	ENST00000377045.9	c.484T>C	p.Ser162Pro	missense_variant	6/16	1	NM_001654.5	P1
ARAF	ENST00000377039.2	c.484T>C	p.Ser162Pro	missense_variant	6/6	2
ARAF	ENST00000489496.1			downstream_gene_variant		5

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 09, 2021

The c.484T>C (p.S162P) alteration is located in exon 6 (coding exon 5) of the ARAF gene. This alteration results from a T to C substitution at nucleotide position 484, causing the serine (S) at amino acid position 162 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.0022	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T;T;.
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.58	T;T;T
M_CAP	Uncertain	0.087	D
MetaRNN	Benign	0.080	T;T;T
MetaSVM	Benign	-0.32	T
MutationAssessor	Benign	1.4	.;L;L
MutationTaster	Benign	0.73	N;N;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.55	N;N;N
REVEL	Benign	0.18
Sift	Benign	0.19	T;T;T
Sift4G	Benign	0.30	T;T;T
Polyphen		0.0060	.;B;.
Vest4		0.25
MutPred		0.15		.;Loss of stability (P = 0.0928);Loss of stability (P = 0.0928);
MVP		0.71
MPC		0.094
ClinPred		0.091	T
GERP RS		1.8
Varity_R		0.12
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chrX-47424676;