X-47566731-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001654.5(ARAF):ā€‹c.650A>Gā€‹(p.Asn217Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000913 in 1,095,397 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 22)
Exomes š‘“: 9.1e-7 ( 0 hom. 1 hem. )

Consequence

ARAF
NM_001654.5 missense

Scores

2
9
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.18
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ARAFNM_001654.5 linkuse as main transcriptc.650A>G p.Asn217Ser missense_variant 7/16 ENST00000377045.9
ARAFNM_001256196.2 linkuse as main transcriptc.659A>G p.Asn220Ser missense_variant 7/16

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ARAFENST00000377045.9 linkuse as main transcriptc.650A>G p.Asn217Ser missense_variant 7/161 NM_001654.5 P1P10398-1

Frequencies

GnomAD3 genomes
Cov.:
22
GnomAD4 exome
AF:
9.13e-7
AC:
1
AN:
1095397
Hom.:
0
Cov.:
32
AF XY:
0.00000277
AC XY:
1
AN XY:
361163
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000119
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
22

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMar 14, 2023The c.650A>G (p.N217S) alteration is located in exon 7 (coding exon 6) of the ARAF gene. This alteration results from a A to G substitution at nucleotide position 650, causing the asparagine (N) at amino acid position 217 to be replaced by a serine (S). 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
Uncertain
0.48
BayesDel_addAF
Benign
-0.15
T
BayesDel_noAF
Benign
-0.45
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.34
T;D
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.95
D;D
M_CAP
Pathogenic
0.63
D
MetaRNN
Uncertain
0.57
D;D
MetaSVM
Uncertain
-0.19
T
MutationAssessor
Uncertain
2.7
.;M
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.56
T
PROVEAN
Uncertain
-2.8
.;D
REVEL
Uncertain
0.42
Sift
Benign
0.070
.;T
Sift4G
Benign
0.064
T;T
Polyphen
0.88
.;P
Vest4
0.48
MutPred
0.25
.;Loss of loop (P = 0.0203);
MVP
0.91
MPC
0.14
ClinPred
0.95
D
GERP RS
5.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.44
gMVP
0.57

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.060
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-47426130; API