15-90889880-A-G

Position:

• chr15-90889880-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002005.4(FES):​c.967A>G​(p.Met323Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00317 in 1,613,452 control chromosomes in the GnomAD database, including 126 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.014 (64 hom., cov: 31)
  • Exomes 𝑓: 0.0020 (62 hom.)
• Consequence: FES NM_002005.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.561

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]

FES (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0021565259).
• BP6: Variant 15-90889880-A-G is Benign according to our data. Variant chr15-90889880-A-G is described in ClinVar as [Benign]. Clinvar id is 773300.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0514 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FES	NM_002005.4	c.967A>G	p.Met323Val	missense_variant	8/19	ENST00000328850.8	NP_001996.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FES	ENST00000328850.8	c.967A>G	p.Met323Val	missense_variant	8/19	1	NM_002005.4	ENSP00000331504.3

Frequencies

GnomAD3 genomes AF: 0.0143 AC: 2168 AN: 151692 Hom.: 63 Cov.: 31

Gnomad AFR AF: 0.0471

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00938

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000618

Gnomad OTH AF: 0.0159

GnomAD3 exomes AF: 0.00413 AC: 1038 AN: 251164 Hom.: 27 AF XY: 0.00334 AC XY: 453 AN XY: 135776

Gnomad AFR exome AF: 0.0476

Gnomad AMR exome AF: 0.00434

Gnomad ASJ exome AF: 0.000695

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000425

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000598

Gnomad OTH exome AF: 0.00424

GnomAD4 exome AF: 0.00201 AC: 2933 AN: 1461640 Hom.: 62 Cov.: 31 AF XY: 0.00185 AC XY: 1342 AN XY: 727100

Gnomad4 AFR exome AF: 0.0534

Gnomad4 AMR exome AF: 0.00458

Gnomad4 ASJ exome AF: 0.000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000325

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000489

Gnomad4 OTH exome AF: 0.00502

GnomAD4 genome AF: 0.0143 AC: 2177 AN: 151812 Hom.: 64 Cov.: 31 AF XY: 0.0143 AC XY: 1063 AN XY: 74156

Gnomad4 AFR AF: 0.0472

Gnomad4 AMR AF: 0.00937

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000618

Gnomad4 OTH AF: 0.0157

Alfa AF: 0.00228 Hom.: 9

Bravo AF: 0.0161

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.0485 AC: 213

ESP6500EA AF: 0.000582 AC: 5

ExAC AF: 0.00488 AC: 593

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.000709

EpiControl AF: 0.000948

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 12, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	4.7
DANN	Benign	0.33
DEOGEN2	Benign	0.097	T;.;T;.;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.61	T;T;T;T;T
MetaRNN	Benign	0.0022	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L;.;.;.;L
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.31	N;N;N;N;N
REVEL	Benign	0.10
Sift	Benign	0.28	T;T;T;T;T
Sift4G	Benign	0.28	T;T;T;T;T
Polyphen		0.0	B;B;B;B;B
Vest4		0.081
MVP		0.49
MPC		0.33
ClinPred		0.0060	T
GERP RS		-4.0
Varity_R		0.076
gMVP		0.12

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: rs56296062; hg19: chr15-91433110;