18-756629-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_005433.4(YES1):c.199G>A(p.Gly67Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000366 in 1,614,192 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00071 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00033 (1 hom.)
• Consequence: YES1 NM_005433.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.32

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

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015033752).
• BS2: High AC in GnomAd at 108 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
YES1	NM_005433.4	c.199G>A	p.Gly67Arg	missense_variant	2/12	ENST00000314574.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
YES1	ENST00000314574.5	c.199G>A	p.Gly67Arg	missense_variant	2/12	1	NM_005433.4	P1

Frequencies

GnomAD3 genomes AF: 0.000710 AC: 108 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.0703

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000262 AC: 66 AN: 251472 Hom.: 0 AF XY: 0.000294 AC XY: 40 AN XY: 135912

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000116

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: 0.000527

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000330 AC: 483 AN: 1461878 Hom.: 1 Cov.: 31 AF XY: 0.000297 AC XY: 216 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000409

Gnomad4 OTH exome AF: 0.000364

GnomAD4 genome AF: 0.000709 AC: 108 AN: 152314 Hom.: 0 Cov.: 32 AF XY: 0.000712 AC XY: 53 AN XY: 74490

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000470

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000416 Hom.: 0

Bravo AF: 0.000937

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000296 AC: 36

EpiCase AF: 0.000545

EpiControl AF: 0.000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 26, 2022

The c.199G>A (p.G67R) alteration is located in exon 2 (coding exon 1) of the YES1 gene. This alteration results from a G to A substitution at nucleotide position 199, causing the glycine (G) at amino acid position 67 to be replaced by an arginine (R). 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	0.32
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.15
Cadd	Benign	23
Dann	Uncertain	0.99
Eigen	Benign	-0.013
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.88	D;.;D
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.015	T;T;T
MetaSVM	Benign	-0.61	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.61	T
Sift4G	Benign	0.095	T;T;T
Polyphen		0.0070	.;B;B
Vest4		0.57
MutPred		0.22		.;Gain of solvent accessibility (P = 0.0328);Gain of solvent accessibility (P = 0.0328);
MVP		0.79
MPC		0.69
ClinPred		0.077	T
GERP RS		4.9
Varity_R		0.16
gMVP		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs201966473; hg19: chr18-756629;