chr15-90887276-G-C

Variant names:

• chr15-90887276-G-C
• NM_002005.4:c.574G>C

Variant summary

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

The NM_002005.4(FES):​c.574G>C​(p.Ala192Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: FES NM_002005.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.29

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

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 rank	MANE	Protein	UniProt
FES	NM_002005.4	c.574G>C	p.Ala192Pro	missense_variant	Exon 5 of 19	ENST00000328850.8	NP_001996.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FES	ENST00000328850.8	c.574G>C	p.Ala192Pro	missense_variant	Exon 5 of 19	1	NM_002005.4	ENSP00000331504.3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 56

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 13, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.574G>C (p.A192P) alteration is located in exon 5 (coding exon 4) of the FES gene. This alteration results from a G to C substitution at nucleotide position 574, causing the alanine (A) at amino acid position 192 to be replaced by a proline (P). 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	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T;.;T;.;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.95	D;D;D;D;D
M_CAP	Benign	0.024	T
MetaRNN	Uncertain	0.70	D;D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L;.;.;.;L
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-2.1	N;N;N;N;N
REVEL	Benign	0.19
Sift	Uncertain	0.023	D;T;D;D;D
Sift4G	Benign	0.18	T;T;T;T;T
Polyphen		0.96	D;D;D;D;D
Vest4		0.77
MutPred		0.29		Loss of MoRF binding (P = 0.0659);.;.;.;Loss of MoRF binding (P = 0.0659);
MVP		0.75
MPC		0.93
ClinPred		0.90	D
GERP RS		3.9
Varity_R		0.88
gMVP		0.54

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-91430506;