X-47563271-G-C

Position:

• chrX-47563271-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001654.5(ARAF):​c.142G>C​(p.Ala48Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: ARAF NM_001654.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.50

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.917

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARAF	NM_001654.5	c.142G>C	p.Ala48Pro	missense_variant	3/16	ENST00000377045.9
ARAF	NM_001256196.2	c.142G>C	p.Ala48Pro	missense_variant	3/16
ARAF	NM_001256197.2	c.142G>C	p.Ala48Pro	missense_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARAF	ENST00000377045.9	c.142G>C	p.Ala48Pro	missense_variant	3/16	1	NM_001654.5	P1
ARAF	ENST00000377039.2	c.142G>C	p.Ala48Pro	missense_variant	3/6	2
ARAF	ENST00000489496.1	n.62G>C		non_coding_transcript_exon_variant	2/4	5

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

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

Mar 31, 2024

The c.142G>C (p.A48P) alteration is located in exon 3 (coding exon 2) of the ARAF gene. This alteration results from a G to C substitution at nucleotide position 142, causing the alanine (A) at amino acid position 48 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	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.65	D
BayesDel_noAF	Pathogenic	0.69
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T;D;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.97	D;D;D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.92	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.6	.;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-4.8	D;D;D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.017	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.80
MutPred		0.74		Gain of loop (P = 0.0312);Gain of loop (P = 0.0312);Gain of loop (P = 0.0312);
MVP		1.0
MPC		2.5
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.98
gMVP		0.99

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-47422670;