2-73847718-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_213622.4(STAMBP):c.707C>T(p.Ser236Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000547 in 1,461,702 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: STAMBP NM_213622.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.86

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-73847718-C-T is Pathogenic according to our data. Variant chr2-73847718-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 492960.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.41873497).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STAMBP	NM_213622.4	c.707C>T	p.Ser236Phe	missense_variant	5/10	ENST00000394070.7
LOC112268419	XR_007087106.1	n.358-8816G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STAMBP	ENST00000394070.7	c.707C>T	p.Ser236Phe	missense_variant	5/10	1	NM_213622.4	P4
	ENST00000650890.1	n.346-8816G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 250576 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135364

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

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: 0.00000547 AC: 8 AN: 1461702 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727164

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Microcephaly-capillary malformation syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

case-control

Department Of Pediatrics And Neonatology, Nagoya City University Graduate School Of Medical Sciences

Jan 02, 2018

The mutation is located in the SH3 binding motif with which SH3 domain of STAM interacts. The mutation was predicted to be damaging by SIFT (score 0.003), PolyPhen-2 (HDIV score 0.748) and MutationTaster (probability value 0.999). The raw CADD score was 6.85 and scaled C-score was 33, indicating pathogenicity. The mutation was not registered in the 1000 Genomes Project, ESP6500, HGVD, UK10K, HGMD (ver2017.3) and ClinVar databases as of December 2017. Only 3 out of 60,543 individuals (MAF = 0.00005) and 1 out of 3,545 individuals (MAF = 0.00028) carried the mutation as heterozygote in ExAC and iJGVD (3.5K Japanese) database, respectively. Homozygous carriers of the mutation have not been registered in any database. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Benign	-0.079	T
BayesDel_noAF	Benign	-0.090
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D;D;.;D;D
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.42	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;L;.;L;L
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-4.7	D;D;D;D;D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0030	D;D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D
Polyphen		0.75	P;P;.;P;P
Vest4		0.56
MutPred		0.35		Loss of disorder (P = 0.0048);Loss of disorder (P = 0.0048);Loss of disorder (P = 0.0048);Loss of disorder (P = 0.0048);Loss of disorder (P = 0.0048);
MVP		0.56
MPC		1.1
ClinPred		0.76	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.69
gMVP		0.83

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

LitVar

Other links and lift over

dbSNP: rs766580482; hg19: chr2-74074845; COSMIC: COSV59898119; COSMIC: COSV59898119;