rs143739249

Variant names:

• chr2-73830968-C-G
• rs143739249
• NM_213622.4:c.112C>G

Your query was ambiguous. Multiple possible variants found:

• chr2-73830968-C-G
• chr2-73830968-C-T
• chr2-73830968-C-A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_213622.4(STAMBP):​c.112C>G​(p.Arg38Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R38H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: STAMBP NM_213622.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 2.94
• Publications: 0 publications found

Genes affected

STAMBP (HGNC:16950): (STAM binding protein) Cytokine-mediated signal transduction in the JAK-STAT cascade requires the involvement of adaptor molecules. One such signal-transducing adaptor molecule contains an SH3 domain that is required for induction of MYC and cell growth. The protein encoded by this gene binds to the SH3 domain of the signal-transducing adaptor molecule, and plays a critical role in cytokine-mediated signaling for MYC induction and cell cycle progression. Multiple alternatively spliced transcript variants encoding the same protein isoform have been found for this gene. [provided by RefSeq, Jul 2008]

STAMBP Gene-Disease associations (from GenCC):

• microcephaly-capillary malformation syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet, G2P

ENSG00000293671 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_213622.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-73830968-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 50793.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.907

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_213622.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STAMBP	NM_213622.4	MANE Select	c.112C>G	p.Arg38Gly	missense	Exon 2 of 10	NP_998787.1	O95630-1
	STAMBP	NM_001353967.2		c.112C>G	p.Arg38Gly	missense	Exon 3 of 11	NP_001340896.1	A0A140VK54
	STAMBP	NM_001353968.2		c.112C>G	p.Arg38Gly	missense	Exon 2 of 10	NP_001340897.1	A0A140VK54

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STAMBP	ENST00000394070.7	TSL:1 MANE Select	c.112C>G	p.Arg38Gly	missense	Exon 2 of 10	ENSP00000377633.2	O95630-1
	STAMBP	ENST00000394073.6	TSL:1	c.112C>G	p.Arg38Gly	missense	Exon 3 of 11	ENSP00000377636.1	O95630-1
	STAMBP	ENST00000683877.1		c.112C>G	p.Arg38Gly	missense	Exon 3 of 11	ENSP00000507446.1	A0A804HJC8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Microcephaly-capillary malformation syndrome (2)
-	2	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.91	D
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Benign	-0.46	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		2.9
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Uncertain	0.48
Sift	Benign	0.066	T
Sift4G	Uncertain	0.057	T
Polyphen		0.99	D
Vest4		0.95
MutPred		0.82		Gain of glycosylation at S39 (P = 0.0225)
MVP		0.74
MPC		1.1
ClinPred		0.99	D
GERP RS		2.9
PromoterAI		-0.14	Neutral
Varity_R		0.70
gMVP		0.83
Mutation Taster		=4/96	disease causing

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

Other links and lift over

dbSNP: rs143739249; hg19: chr2-74058095;