10-17696791-A-G

Variant names:

• chr10-17696791-A-G
• NM_003473.4:c.745A>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003473.4(STAM):​c.745A>G​(p.Lys249Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: STAM NM_003473.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.28

Genes affected

STAM (HGNC:11357): (signal transducing adaptor molecule) This gene encodes a member of the signal-transducing adaptor molecule family. These proteins mediate downstream signaling of cytokine receptors and also play a role in ER to Golgi trafficking by interacting with the coat protein II complex. The encoded protein also associates with hepatocyte growth factor-regulated substrate to form the endosomal sorting complex required for transport-0 (ESCRT-0), which sorts ubiquitinated membrane proteins to the ESCRT-1 complex for lysosomal degradation. Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, Feb 2011]

ENSG00000229190 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STAM	NM_003473.4	c.745A>G	p.Lys249Glu	missense_variant	Exon 8 of 14	ENST00000377524.8	NP_003464.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STAM	ENST00000377524.8	c.745A>G	p.Lys249Glu	missense_variant	Exon 8 of 14	1	NM_003473.4	ENSP00000366746.3
STAM	ENST00000377500.1	c.412A>G	p.Lys138Glu	missense_variant	Exon 5 of 6	5		ENSP00000366721.1
STAM	ENST00000494250.1	n.333A>G		non_coding_transcript_exon_variant	Exon 2 of 3	3
ENSG00000229190	ENST00000445235.1	n.45-88T>C		intron_variant	Intron 1 of 2	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.745A>G (p.K249E) alteration is located in exon 8 (coding exon 8) of the STAM gene. This alteration results from a A to G substitution at nucleotide position 745, causing the lysine (K) at amino acid position 249 to be replaced by a glutamic acid (E). 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	0.87
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T;T
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.027	D
MetaRNN	Uncertain	0.50	T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	-1.3	N;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.5	D;.
REVEL	Uncertain	0.49
Sift	Uncertain	0.011	D;.
Sift4G	Uncertain	0.016	D;D
Polyphen		1.0	D;.
Vest4		0.72
MutPred		0.48		Loss of methylation at K249 (P = 0.0037);.;
MVP		0.70
MPC		0.52
ClinPred		0.98	D
GERP RS		6.2
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.52
gMVP		0.66

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-17738790;