18-739808-C-T

Variant names:

• chr18-739808-C-T
• rs1348485947
• NM_005433.4:c.1064G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_Moderate BS2

The NM_005433.4(YES1):​c.1064G>A​(p.Ser355Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000055 in 1,455,442 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: YES1 NM_005433.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.76

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]

ENSG00000264635 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.875
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
YES1	NM_005433.4	c.1064G>A	p.Ser355Asn	missense_variant	Exon 9 of 12	ENST00000314574.5	NP_005424.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
YES1	ENST00000314574.5	c.1064G>A	p.Ser355Asn	missense_variant	Exon 9 of 12	1	NM_005433.4	ENSP00000324740.4
YES1	ENST00000584307.5	c.1064G>A	p.Ser355Asn	missense_variant	Exon 9 of 12	1		ENSP00000462468.1
YES1	ENST00000577961.5	c.1079G>A	p.Ser360Asn	missense_variant	Exon 9 of 12	5		ENSP00000464380.1
ENSG00000264635	ENST00000581712.1	n.-146G>A		upstream_gene_variant		6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000163 AC: 4 AN: 245874 Hom.: 0 AF XY: 0.0000151 AC XY: 2 AN XY: 132750

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000120

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: 0.00000550 AC: 8 AN: 1455442 Hom.: 0 Cov.: 29 AF XY: 0.00000415 AC XY: 3 AN XY: 723744

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000912

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1064G>A (p.S355N) alteration is located in exon 9 (coding exon 8) of the YES1 gene. This alteration results from a G to A substitution at nucleotide position 1064, causing the serine (S) at amino acid position 355 to be replaced by an asparagine (N). 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	0.90
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.31
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	.;D;D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;.;D
M_CAP	Benign	0.0068	T
MetaRNN	Pathogenic	0.88	D;D;D
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.7	.;L;L
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-2.7	.;.;D
REVEL	Benign	0.29
Sift	Pathogenic	0.0	.;.;D
Sift4G	Benign	0.11	T;T;T
Polyphen		0.86	.;P;P
Vest4		0.81
MutPred		0.76		.;Gain of relative solvent accessibility (P = 0.09);Gain of relative solvent accessibility (P = 0.09);
MVP		0.63
MPC		0.39
ClinPred		0.61	D
GERP RS		5.7
Varity_R		0.62
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs1348485947; hg19: chr18-739808;