18-745710-G-T

Variant names:

• chr18-745710-G-T
• rs757945173
• NM_005433.4:c.722C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005433.4(YES1):​c.722C>A​(p.Thr241Lys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,455,938 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. T241R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: YES1 NM_005433.4 missense, splice_region
• Scores: Splicing: ADA: 0.01115
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.59
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21616533).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005433.4. 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
	YES1	NM_005433.4	MANE Select	c.722C>A	p.Thr241Lys	missense splice_region	Exon 6 of 12	NP_005424.1	P07947

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	YES1	ENST00000314574.5	TSL:1 MANE Select	c.722C>A	p.Thr241Lys	missense splice_region	Exon 6 of 12	ENSP00000324740.4	P07947
	YES1	ENST00000584307.5	TSL:1	c.722C>A	p.Thr241Lys	missense splice_region	Exon 6 of 12	ENSP00000462468.1	P07947
	YES1	ENST00000577961.5	TSL:5	c.737C>A	p.Thr246Lys	missense splice_region	Exon 6 of 12	ENSP00000464380.1	J3QRU1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000406 AC: 1 AN: 246164 AF XY: 0.00000752

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1455938 Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 2 AN XY: 724066

African (AFR) AF: 0.00 AC: 0 AN: 33228

American (AMR) AF: 0.00 AC: 0 AN: 43378

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25904

East Asian (EAS) AF: 0.00 AC: 0 AN: 39572

South Asian (SAS) AF: 0.00 AC: 0 AN: 84454

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53052

Middle Eastern (MID) AF: 0.000355 AC: 2 AN: 5628

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110528

Other (OTH) AF: 0.00 AC: 0 AN: 60194

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.061	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	24
DANN	Benign	0.91
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.047
Eigen_PC	Benign	0.21
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.14	N
PhyloP100		7.6
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-0.30	N
REVEL	Benign	0.17
Sift	Benign	0.50	T
Sift4G	Benign	0.64	T
Polyphen		0.0020	B
Vest4		0.55
MutPred		0.32		Gain of ubiquitination at T241 (P = 0.0311)
MVP		0.19
MPC		0.37
ClinPred		0.80	D
GERP RS		5.6
Varity_R		0.35
gMVP		0.54
Mutation Taster		=61/39	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.011
dbscSNV1_RF	Benign	0.13
SpliceAI score (max)		0.010		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: rs757945173; hg19: chr18-745710;