15-90886998-A-T

Variant names:

• chr15-90886998-A-T
• rs756081466
• NM_002005.4:c.425A>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002005.4(FES):​c.425A>T​(p.Tyr142Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,614,046 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: FES NM_002005.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.33
• Publications: 0 publications found

Genes affected

FES (HGNC:3657): (FES proto-oncogene, tyrosine kinase) This gene encodes the human cellular counterpart of a feline sarcoma retrovirus protein with transforming capabilities. The gene product has tyrosine-specific protein kinase activity and that activity is required for maintenance of cellular transformation. Its chromosomal location has linked it to a specific translocation event identified in patients with acute promyelocytic leukemia but it is also involved in normal hematopoiesis as well as growth factor and cytokine receptor signaling. Alternative splicing results in multiple variants encoding different isoforms.[provided by RefSeq, Jan 2009]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38959417).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002005.4. 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
	FES	NM_002005.4	MANE Select	c.425A>T	p.Tyr142Phe	missense	Exon 4 of 19	NP_001996.1	P07332-1
	FES	NM_001143783.1		c.251A>T	p.Tyr84Phe	missense	Exon 2 of 17	NP_001137255.1	P07332-3
	FES	NM_001143784.1		c.425A>T	p.Tyr142Phe	missense	Exon 3 of 17	NP_001137256.1	P07332-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FES	ENST00000328850.8	TSL:1 MANE Select	c.425A>T	p.Tyr142Phe	missense	Exon 4 of 19	ENSP00000331504.3	P07332-1
	FES	ENST00000394300.7	TSL:1	c.251A>T	p.Tyr84Phe	missense	Exon 2 of 17	ENSP00000377837.3	P07332-3
	FES	ENST00000444422.2	TSL:1	c.425A>T	p.Tyr142Phe	missense	Exon 3 of 17	ENSP00000400868.2	P07332-4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152232 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000797 AC: 2 AN: 251092 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

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: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461814 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727208

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53352

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1112006

Other (OTH) AF: 0.0000331 AC: 2 AN: 60392

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152232 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 74374

African (AFR) AF: 0.00 AC: 0 AN: 41458

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Benign	0.0056	T
BayesDel_noAF	Benign	-0.23
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	T
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-0.51	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		8.3
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.25
Sift	Benign	0.058	T
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.71
MutPred		0.30		Loss of methylation at K137 (P = 0.0538)
MVP		0.77
MPC		1.0
ClinPred		0.83	D
GERP RS		4.9
Varity_R		0.52
gMVP		0.37

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: rs756081466; hg19: chr15-91430228;