X-47567066-C-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001654.5(ARAF):​c.808C>G​(p.Pro270Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000178 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.000018 (0 hom., 1 hem., cov: 23)
• Consequence: ARAF NM_001654.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.41
• Publications: 1 publications found

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]

ARAF Gene-Disease associations (from GenCC):

• diffuse lymphatic malformation

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20252967).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001654.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARAF	NM_001654.5	MANE Select	c.808C>G	p.Pro270Ala	missense	Exon 9 of 16	NP_001645.1	A0A024R178
	ARAF	NM_001256196.2		c.817C>G	p.Pro273Ala	missense	Exon 9 of 16	NP_001243125.1	Q96II5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARAF	ENST00000377045.9	TSL:1 MANE Select	c.808C>G	p.Pro270Ala	missense	Exon 9 of 16	ENSP00000366244.4	P10398-1
	ARAF	ENST00000895646.1		c.808C>G	p.Pro270Ala	missense	Exon 9 of 16	ENSP00000565705.1
	ARAF	ENST00000895654.1		c.841C>G	p.Pro281Ala	missense	Exon 9 of 16	ENSP00000565713.1

Frequencies

GnomAD3 genomes AF: 0.0000178 AC: 2 AN: 112295 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000648

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: 0.0000178 AC: 2 AN: 112295 Hom.: 0 Cov.: 23 AF XY: 0.0000290 AC XY: 1 AN XY: 34435

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

African (AFR) AF: 0.0000648 AC: 2 AN: 30858

American (AMR) AF: 0.00 AC: 0 AN: 10673

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2653

East Asian (EAS) AF: 0.00 AC: 0 AN: 3584

South Asian (SAS) AF: 0.00 AC: 0 AN: 2739

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6109

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53238

Other (OTH) AF: 0.00 AC: 0 AN: 1520

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.28	T
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.078	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	1.7	L
PhyloP100		2.4
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.90	N
REVEL	Benign	0.17
Sift	Benign	0.15	T
Sift4G	Benign	0.12	T
Polyphen		0.024	B
Vest4		0.33
MutPred		0.22		Loss of glycosylation at P270 (P = 0.02)
MVP		0.73
MPC		0.097
ClinPred		0.19	T
GERP RS		3.9
Varity_R		0.14
gMVP		0.51
Mutation Taster		=80/20	polymorphism

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

Other links and lift over

dbSNP: rs923151586; hg19: chrX-47426465;