22-40827097-T-A

Variant names:

• chr22-40827097-T-A
• rs1299307424
• NM_003932.5:c.980A>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003932.5(ST13):​c.980A>T​(p.Gln327Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000685 in 1,459,320 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ST13 NM_003932.5 missense, splice_region
• Scores: Splicing: ADA: 0.5887
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.80

Genes affected

ST13 (HGNC:11343): (ST13 Hsp70 interacting protein) The protein encoded by this gene is an adaptor protein that mediates the association of the heat shock proteins HSP70 and HSP90. This protein has been shown to be involved in the assembly process of glucocorticoid receptor, which requires the assistance of multiple molecular chaperones. The expression of this gene is reported to be downregulated in colorectal carcinoma tissue suggesting that it is a candidate tumor suppressor gene. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jun 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3689954).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ST13	NM_003932.5	c.980A>T	p.Gln327Leu	missense_variant, splice_region_variant	Exon 11 of 12	ENST00000216218.8	NP_003923.2
ST13	NM_001278589.2	c.950A>T	p.Gln317Leu	missense_variant, splice_region_variant	Exon 11 of 12		NP_001265518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ST13	ENST00000216218.8	c.980A>T	p.Gln327Leu	missense_variant, splice_region_variant	Exon 11 of 12	1	NM_003932.5	ENSP00000216218.3
ST13	ENST00000455824.1	n.*729A>T		downstream_gene_variant		5		ENSP00000397062.1
ST13	ENST00000480048.5	n.*53A>T		downstream_gene_variant		4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459320 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 725968

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: 9.00e-7

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

Jan 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.980A>T (p.Q327L) alteration is located in exon 11 (coding exon 11) of the ST13 gene. This alteration results from a A to T substitution at nucleotide position 980, causing the glutamine (Q) at amino acid position 327 to be replaced by a leucine (L). 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	0.98
BayesDel_addAF	Benign	-0.033	T
BayesDel_noAF	Benign	-0.29
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	T
Eigen	Benign	0.067
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-0.96	T
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.9	D
REVEL	Benign	0.21
Sift	Benign	0.035	D
Sift4G	Uncertain	0.028	D
Polyphen		0.043	B
Vest4		0.58
MutPred		0.28		Loss of disorder (P = 0.0411);
MVP		0.61
MPC		0.52
ClinPred		0.97	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.37
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.59
dbscSNV1_RF	Benign	0.46
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

LitVar

Other links and lift over

dbSNP: rs1299307424; hg19: chr22-41223101;