Genetic Variant ARAF:p.His191Tyr (chrX-47566652-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001654.5(ARAF):c.571C>T(p.His191Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000827 in 1,172,409 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 33 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 0.000063 ( 0 hom., 2 hem., cov: 22)

Exomes 𝑓: 0.000085 ( 0 hom. 31 hem. )

Consequence

ARAF
NM_001654.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.14

Publications

1 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: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.033817887).

BS2

High AC in GnomAd4 at 7 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.571C>T	p.His191Tyr	missense	Exon 7 of 16	NP_001645.1	A0A024R178
	ARAF	NM_001256196.2		c.580C>T	p.His194Tyr	missense	Exon 7 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.571C>T	p.His191Tyr	missense	Exon 7 of 16	ENSP00000366244.4	P10398-1
ARAF	ENST00000895646.1		c.571C>T	p.His191Tyr	missense	Exon 7 of 16	ENSP00000565705.1
ARAF	ENST00000895654.1		c.604C>T	p.His202Tyr	missense	Exon 7 of 16	ENSP00000565713.1

Frequencies

GnomAD3 genomes

AF:

0.0000630

AC:

AN:

111102

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000329

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000757

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000756

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000479

AC:

AN:

146259

AF XY:

0.0000890

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000745

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000608

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000848

AC:

AN:

1061307

Hom.:

Cov.:

AF XY:

0.0000907

AC XY:

AN XY:

341781

show subpopulations

African (AFR)

AF:

0.0000781

AC:

AN:

25603

American (AMR)

AF:

0.0000638

AC:

AN:

31340

Ashkenazi Jewish (ASJ)

AF:

0.000606

AC:

AN:

16509

East Asian (EAS)

AF:

0.00

AC:

AN:

29824

South Asian (SAS)

AF:

0.00

AC:

AN:

48350

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39050

Middle Eastern (MID)

AF:

0.00229

AC:

AN:

3924

European-Non Finnish (NFE)

AF:

0.0000766

AC:

AN:

822241

Other (OTH)

AF:

0.0000900

AC:

AN:

44466

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

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:

0.0000630

AC:

AN:

111102

Hom.:

Cov.:

AF XY:

0.0000601

AC XY:

AN XY:

33276

show subpopulations

African (AFR)

AF:

0.0000329

AC:

AN:

30428

American (AMR)

AF:

0.00

AC:

AN:

10490

Ashkenazi Jewish (ASJ)

AF:

0.000757

AC:

AN:

2642

East Asian (EAS)

AF:

0.00

AC:

AN:

3534

South Asian (SAS)

AF:

0.00

AC:

AN:

2652

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6011

Middle Eastern (MID)

AF:

0.00

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.0000756

AC:

AN:

52937

Other (OTH)

AF:

0.00

AC:

AN:

1492

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.545

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.000131

Hom.:

Bravo

AF:

0.0000718

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000346

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.0000664

AC:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.59

CADD

Benign

(source)

DANN

Benign

0.33

DEOGEN2

Benign

0.23

FATHMM_MKL

Benign

0.76

LIST_S2

Benign

0.83

M_CAP

Benign

0.020

MetaRNN

Benign

0.034

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.1

PhyloP100

1.1

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.19

REVEL

Benign

0.059

Sift

Benign

0.94

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.14

MVP

0.61

MPC

0.089

ClinPred

0.019

GERP RS

2.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.072

gMVP

0.40

Mutation Taster

=98/2

polymorphism

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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