15-90889880-A-T

Variant names:

• chr15-90889880-A-T
• rs56296062
• NM_002005.4:c.967A>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002005.4(FES):​c.967A>T​(p.Met323Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,334 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M323V) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FES NM_002005.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.561
• Publications: 8 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.047762543).

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.967A>T	p.Met323Leu	missense	Exon 8 of 19	NP_001996.1	P07332-1
	FES	NM_001143783.1		c.793A>T	p.Met265Leu	missense	Exon 6 of 17	NP_001137255.1	P07332-3
	FES	NM_001143784.1		c.967A>T	p.Met323Leu	missense	Exon 7 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.967A>T	p.Met323Leu	missense	Exon 8 of 19	ENSP00000331504.3	P07332-1
	FES	ENST00000394300.7	TSL:1	c.793A>T	p.Met265Leu	missense	Exon 6 of 17	ENSP00000377837.3	P07332-3
	FES	ENST00000444422.2	TSL:1	c.967A>T	p.Met323Leu	missense	Exon 7 of 17	ENSP00000400868.2	P07332-4

Frequencies

GnomAD3 genomes AF: 0.0000264 AC: 4 AN: 151694 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000970

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461640 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727100

African (AFR) AF: 0.0000299 AC: 1 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: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53192

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111992

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome AF: 0.0000264 AC: 4 AN: 151694 Hom.: 0 Cov.: 31 AF XY: 0.0000405 AC XY: 3 AN XY: 74028

African (AFR) AF: 0.0000970 AC: 4 AN: 41240

American (AMR) AF: 0.00 AC: 0 AN: 15248

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5134

South Asian (SAS) AF: 0.00 AC: 0 AN: 4802

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10562

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67936

Other (OTH) AF: 0.00 AC: 0 AN: 2076

Alfa AF: 0.00 Hom.: 18

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions as Germline

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	Benign	0.10
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	1.5
DANN	Benign	0.43
DEOGEN2	Benign	0.099	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.094	N
LIST_S2	Benign	0.55	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.048	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.63	N
PhyloP100		0.56
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.56	N
REVEL	Benign	0.068
Sift	Benign	0.28	T
Sift4G	Benign	0.30	T
Polyphen		0.0	B
Vest4		0.14
MutPred		0.21		Loss of catalytic residue at V319 (P = 0.0396)
MVP		0.52
MPC		0.30
ClinPred		0.016	T
GERP RS		-4.0
Varity_R		0.11
gMVP		0.097
Mutation Taster		=97/3	polymorphism

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: rs56296062; hg19: chr15-91433110;