NM_001654.5:c.571C>A

Variant names:

• chrX-47566652-C-A
• rs372462744
• NM_001654.5:c.571C>A

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.571C>A​(p.His191Asn) 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. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H191Y) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 22)
• Consequence: ARAF NM_001654.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.14
• 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=0.10464889).

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.571C>A	p.His191Asn	missense	Exon 7 of 16	NP_001645.1	A0A024R178
	ARAF	NM_001256196.2		c.580C>A	p.His194Asn	missense	Exon 7 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.571C>A	p.His191Asn	missense	Exon 7 of 16	ENSP00000366244.4	P10398-1
	ARAF	ENST00000895646.1		c.571C>A	p.His191Asn	missense	Exon 7 of 16	ENSP00000565705.1
	ARAF	ENST00000895654.1		c.604C>A	p.His202Asn	missense	Exon 7 of 16	ENSP00000565713.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	15
DANN	Benign	0.84
DEOGEN2	Benign	0.26	T
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		1.1
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.10
Sift	Benign	0.36	T
Sift4G	Benign	0.31	T
Polyphen		0.037	B
Vest4		0.17
MutPred		0.14		Loss of catalytic residue at H191 (P = 0.0269)
MVP		0.71
MPC		0.082
ClinPred		0.073	T
GERP RS		2.4
Varity_R		0.13
gMVP		0.36
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs372462744; hg19: chrX-47426051;