chr15-90886998-A-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002005.4(FES):​c.425A>G​(p.Tyr142Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y142F) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 34)
• Consequence: FES NM_002005.4 missense
• Clinical Significance: Not reported in ClinVar
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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>G	p.Tyr142Cys	missense	Exon 4 of 19	NP_001996.1	P07332-1
	FES	NM_001143783.1		c.251A>G	p.Tyr84Cys	missense	Exon 2 of 17	NP_001137255.1	P07332-3
	FES	NM_001143784.1		c.425A>G	p.Tyr142Cys	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>G	p.Tyr142Cys	missense	Exon 4 of 19	ENSP00000331504.3	P07332-1
	FES	ENST00000394300.7	TSL:1	c.251A>G	p.Tyr84Cys	missense	Exon 2 of 17	ENSP00000377837.3	P07332-3
	FES	ENST00000444422.2	TSL:1	c.425A>G	p.Tyr142Cys	missense	Exon 3 of 17	ENSP00000400868.2	P07332-4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251092 AF XY: 0.00

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 Cov.: 32

GnomAD4 genome Cov.: 34

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.20	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Benign	-0.41	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		8.3
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-7.4	D
REVEL	Uncertain	0.47
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.30		Loss of methylation at K137 (P = 0.049)
MVP		0.90
MPC		1.2
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.92
gMVP		0.67

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;