X-47565335-C-A

Variant names:

• chrX-47565335-C-A
• rs143159753
• NM_001654.5:c.542C>A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM1 BP4_Strong BS2

The NM_001654.5(ARAF):​c.542C>A​(p.Thr181Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00111 in 1,208,966 control chromosomes in the GnomAD database, including 1 homozygotes. There are 414 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., 49 hem., cov: 23)
  • Exomes 𝑓: 0.0011 (0 hom. 365 hem.)
• Consequence: ARAF NM_001654.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.96

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• PM1: In a modified_residue Phosphothreonine (size 0) in uniprot entity ARAF_HUMAN
• BP4: Computational evidence support a benign effect (MetaRNN=0.017808765).
• BS2: High Hemizygotes in GnomAd4 at 49 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARAF	NM_001654.5	c.542C>A	p.Thr181Asn	missense_variant	Exon 6 of 16	ENST00000377045.9	NP_001645.1
ARAF	NM_001256196.2	c.551C>A	p.Thr184Asn	missense_variant	Exon 6 of 16		NP_001243125.1
ARAF	NM_001256197.2	c.542C>A	p.Thr181Asn	missense_variant	Exon 6 of 6		NP_001243126.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARAF	ENST00000377045.9	c.542C>A	p.Thr181Asn	missense_variant	Exon 6 of 16	1	NM_001654.5	ENSP00000366244.4
ARAF	ENST00000377039.2	c.542C>A	p.Thr181Asn	missense_variant	Exon 6 of 6	2		ENSP00000366238.1
ARAF	ENST00000489496.1	n.*102C>A		downstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.00123 AC: 138 AN: 112005 Hom.: 1 Cov.: 23 AF XY: 0.00143 AC XY: 49 AN XY: 34167

Gnomad AFR AF: 0.000228

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00683

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: 0.00105

Gnomad OTH AF: 0.00198

GnomAD3 exomes AF: 0.000783 AC: 143 AN: 182592 Hom.: 0 AF XY: 0.000730 AC XY: 49 AN XY: 67138

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00198

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000981

Gnomad OTH exome AF: 0.00200

GnomAD4 exome AF: 0.00110 AC: 1209 AN: 1096908 Hom.: 0 Cov.: 31 AF XY: 0.00101 AC XY: 365 AN XY: 362312

Gnomad4 AFR exome AF: 0.0000758

Gnomad4 AMR exome AF: 0.00179

Gnomad4 ASJ exome AF: 0.000207

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000494

Gnomad4 NFE exome AF: 0.00130

Gnomad4 OTH exome AF: 0.000890

GnomAD4 genome AF: 0.00123 AC: 138 AN: 112058 Hom.: 1 Cov.: 23 AF XY: 0.00143 AC XY: 49 AN XY: 34230

Gnomad4 AFR AF: 0.000227

Gnomad4 AMR AF: 0.00682

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00105

Gnomad4 OTH AF: 0.00196

Alfa AF: 0.000680 Hom.: 3

Bravo AF: 0.00139

ESP6500AA AF: 0.000522 AC: 2

ESP6500EA AF: 0.000892 AC: 6

ExAC AF: 0.000659 AC: 80

EpiCase AF: 0.000819

EpiControl AF: 0.00137

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 23, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.542C>A (p.T181N) alteration is located in exon 6 (coding exon 5) of the ARAF gene. This alteration results from a C to A substitution at nucleotide position 542, causing the threonine (T) at amino acid position 181 to be replaced by an asparagine (N). 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	Benign	0.096
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	T;D;.
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.82	T;T;T
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.018	T;T;T
MetaSVM	Uncertain	0.66	D
MutationAssessor	Uncertain	2.3	.;M;M
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.97	.;N;N
REVEL	Uncertain	0.33
Sift	Benign	0.16	.;T;D
Sift4G	Benign	0.28	T;T;D
Polyphen		0.75	.;P;.
Vest4		0.53
MVP		0.91
MPC		0.16
ClinPred		0.056	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.28
gMVP		0.71

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

LitVar

Other links and lift over

dbSNP: rs143159753; hg19: chrX-47424734;