Genetic Variant ARAF:p.Ser262Ile (chrX-47567043-G-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001654.5(ARAF):c.785G>T(p.Ser262Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000014 in 1,210,387 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000089 ( 0 hom., 2 hem., cov: 23)

Exomes 𝑓: 0.0000064 ( 0 hom. 2 hem. )

Consequence

ARAF
NM_001654.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.717

Publications

0 publications found

Variant links:

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

ARAF links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09069434).

BS2

High AC in GnomAd4 at 10 AD gene.

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.785G>T	p.Ser262Ile	missense	Exon 9 of 16	NP_001645.1	A0A024R178
	ARAF	NM_001256196.2		c.794G>T	p.Ser265Ile	missense	Exon 9 of 16	NP_001243125.1	Q96II5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ARAF	ENST00000377045.9	TSL:1 MANE Select	c.785G>T	p.Ser262Ile	missense	Exon 9 of 16	ENSP00000366244.4	P10398-1
ARAF	ENST00000895646.1		c.785G>T	p.Ser262Ile	missense	Exon 9 of 16	ENSP00000565705.1
ARAF	ENST00000895654.1		c.818G>T	p.Ser273Ile	missense	Exon 9 of 16	ENSP00000565713.1

Frequencies

GnomAD3 genomes

AF:

0.0000890

AC:

AN:

112326

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000324

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

GnomAD2 exomes

AF:

0.0000384

AC:

AN:

182396

AF XY:

0.0000298

show subpopulations

Gnomad AFR exome

AF:

0.000536

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000637

AC:

AN:

1098061

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

363439

show subpopulations

African (AFR)

AF:

0.000189

AC:

AN:

26401

American (AMR)

AF:

0.00

AC:

AN:

35198

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19381

East Asian (EAS)

AF:

0.00

AC:

AN:

30203

South Asian (SAS)

AF:

0.00

AC:

AN:

54136

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40409

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4137

European-Non Finnish (NFE)

AF:

0.00000119

AC:

AN:

842104

Other (OTH)

AF:

0.0000217

AC:

AN:

46092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000890

AC:

AN:

112326

Hom.:

Cov.:

AF XY:

0.0000580

AC XY:

AN XY:

34474

show subpopulations

African (AFR)

AF:

0.000324

AC:

AN:

30831

American (AMR)

AF:

0.00

AC:

AN:

10670

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2652

East Asian (EAS)

AF:

0.00

AC:

AN:

3587

South Asian (SAS)

AF:

0.00

AC:

AN:

2737

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6159

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53258

Other (OTH)

AF:

0.00

AC:

AN:

1509

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.519

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000298

Hom.:

Bravo

AF:

0.000144

ESP6500AA

AF:

0.00104

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000577

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.33

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.56

M_CAP

Benign

0.066

MetaRNN

Benign

0.091

MetaSVM

Benign

-0.83

MutationAssessor

Uncertain

2.0

PhyloP100

0.72

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-2.2

REVEL

Benign

0.14

Sift

Uncertain

0.012

Sift4G

Benign

0.12

Polyphen

0.40

Vest4

0.26

MVP

0.69

MPC

0.094

ClinPred

0.019

GERP RS

0.60

Varity_R

0.097

gMVP

0.60

Mutation Taster

=98/2

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over