NM_005433.4:c.757A>G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_005433.4(YES1):​c.757A>G​(p.Thr253Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,612,840 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

YES1
NM_005433.4 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.63
Variant links:
Genes affected
YES1 (HGNC:12841): (YES proto-oncogene 1, Src family tyrosine kinase) This gene is the cellular homolog of the Yamaguchi sarcoma virus oncogene. The encoded protein has tyrosine kinase activity and belongs to the src family of proteins. This gene lies in close proximity to thymidylate synthase gene on chromosome 18, and a corresponding pseudogene has been found on chromosome 22. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.12657833).
BS2
High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
YES1NM_005433.4 linkc.757A>G p.Thr253Ala missense_variant Exon 7 of 12 ENST00000314574.5 NP_005424.1 P07947

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
YES1ENST00000314574.5 linkc.757A>G p.Thr253Ala missense_variant Exon 7 of 12 1 NM_005433.4 ENSP00000324740.4 P07947
YES1ENST00000584307.5 linkc.757A>G p.Thr253Ala missense_variant Exon 7 of 12 1 ENSP00000462468.1 P07947
YES1ENST00000577961.5 linkc.772A>G p.Thr258Ala missense_variant Exon 7 of 12 5 ENSP00000464380.1 J3QRU1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152210
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
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
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251182
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135786
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000411
AC:
6
AN:
1460630
Hom.:
0
Cov.:
34
AF XY:
0.00000688
AC XY:
5
AN XY:
726632
show subpopulations
Gnomad4 AFR exome
AF:
0.0000598
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152210
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74358
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Feb 20, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.757A>G (p.T253A) alteration is located in exon 7 (coding exon 6) of the YES1 gene. This alteration results from a A to G substitution at nucleotide position 757, causing the threonine (T) at amino acid position 253 to be replaced by an alanine (A). 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
Benign
0.056
BayesDel_addAF
Benign
-0.24
T
BayesDel_noAF
Benign
-0.40
CADD
Benign
23
DANN
Benign
0.68
DEOGEN2
Benign
0.091
.;T;T
Eigen
Benign
-0.24
Eigen_PC
Benign
0.0042
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.87
D;.;D
M_CAP
Benign
0.0051
T
MetaRNN
Benign
0.13
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
-0.67
.;N;N
PrimateAI
Uncertain
0.79
T
PROVEAN
Benign
-0.16
.;.;N
REVEL
Benign
0.14
Sift
Benign
0.78
.;.;T
Sift4G
Benign
0.77
T;T;T
Polyphen
0.0
.;B;B
Vest4
0.39
MutPred
0.24
.;Loss of phosphorylation at T253 (P = 0.0817);Loss of phosphorylation at T253 (P = 0.0817);
MVP
0.40
MPC
0.29
ClinPred
0.11
T
GERP RS
5.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.21
gMVP
0.27

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.20
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.20
Position offset: 6

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs746141725; hg19: chr18-743383; API