18-736862-C-T

Variant names:

• chr18-736862-C-T
• NM_005433.4:c.1237G>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_005433.4(YES1):​c.1237G>A​(p.Ala413Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,474 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: 0.0000014 (0 hom.)
• Consequence: YES1 NM_005433.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.80

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]

ENSG00000266171 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.938

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
YES1	NM_005433.4	c.1237G>A	p.Ala413Thr	missense_variant	Exon 10 of 12	ENST00000314574.5	NP_005424.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
YES1	ENST00000314574.5	c.1237G>A	p.Ala413Thr	missense_variant	Exon 10 of 12	1	NM_005433.4	ENSP00000324740.4
YES1	ENST00000584307.5	c.1237G>A	p.Ala413Thr	missense_variant	Exon 10 of 12	1		ENSP00000462468.1
YES1	ENST00000577961.5	c.1252G>A	p.Ala418Thr	missense_variant	Exon 10 of 12	5		ENSP00000464380.1
ENSG00000266171	ENST00000583314.1	n.1117C>T		non_coding_transcript_exon_variant	Exon 1 of 1	6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460474 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726560

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 08, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1237G>A (p.A413T) alteration is located in exon 10 (coding exon 9) of the YES1 gene. This alteration results from a G to A substitution at nucleotide position 1237, causing the alanine (A) at amino acid position 413 to be replaced by a threonine (T). 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	1.0
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.63	.;D;D
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D;.;D
M_CAP	Benign	0.071	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Uncertain	0.23	D
MutationAssessor	Benign	1.6	.;L;L
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-3.9	.;.;D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	.;.;D
Sift4G	Uncertain	0.035	D;D;D
Polyphen		0.99	.;D;D
Vest4		0.92
MutPred		0.81		.;Loss of stability (P = 0.0662);Loss of stability (P = 0.0662);
MVP		0.95
MPC		0.33
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.89
gMVP		0.78

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr18-736862;