10-17660546-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_003473.4(STAM):c.123T>C(p.Thr41=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0112 in 1,588,300 control chromosomes in the GnomAD database, including 135 homozygotes. 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 Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0083 (11 hom., cov: 32)
  • Exomes 𝑓: 0.012 (124 hom.)
• Consequence: STAM NM_003473.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.00005715
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.53

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 10-17660546-T-C is Benign according to our data. Variant chr10-17660546-T-C is described in ClinVar as [Benign]. Clinvar id is 778035.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0115 (16532/1435990) while in subpopulation MID AF= 0.0347 (197/5672). AF 95% confidence interval is 0.0308. There are 124 homozygotes in gnomad4_exome. There are 8479 alleles in male gnomad4_exome subpopulation. Median coverage is 29. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STAM	NM_003473.4	c.123T>C	p.Thr41=	splice_region_variant, synonymous_variant	2/14	ENST00000377524.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STAM	ENST00000377524.8	c.123T>C	p.Thr41=	splice_region_variant, synonymous_variant	2/14	1	NM_003473.4	P1
STAM	ENST00000377500.1	c.-37+16167T>C		intron_variant		5
STAM	ENST00000445846.1	c.123T>C	p.Thr41=	splice_region_variant, synonymous_variant, NMD_transcript_variant	2/7	4

Frequencies

GnomAD3 genomes AF: 0.00826 AC: 1257 AN: 152192 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00236

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0104

Gnomad ASJ AF: 0.0205

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0160

Gnomad FIN AF: 0.00254

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0116

Gnomad OTH AF: 0.0129

GnomAD3 exomes AF: 0.0105 AC: 2221 AN: 211064 Hom.: 19 AF XY: 0.0115 AC XY: 1322 AN XY: 115186

Gnomad AFR exome AF: 0.00173

Gnomad AMR exome AF: 0.00892

Gnomad ASJ exome AF: 0.0230

Gnomad EAS exome AF: 0.000136

Gnomad SAS exome AF: 0.0190

Gnomad FIN exome AF: 0.00219

Gnomad NFE exome AF: 0.0122

Gnomad OTH exome AF: 0.0122

GnomAD4 exome AF: 0.0115 AC: 16532 AN: 1435990 Hom.: 124 Cov.: 29 AF XY: 0.0119 AC XY: 8479 AN XY: 714360

Gnomad4 AFR exome AF: 0.00292

Gnomad4 AMR exome AF: 0.00750

Gnomad4 ASJ exome AF: 0.0176

Gnomad4 EAS exome AF: 0.000131

Gnomad4 SAS exome AF: 0.0170

Gnomad4 FIN exome AF: 0.00274

Gnomad4 NFE exome AF: 0.0120

Gnomad4 OTH exome AF: 0.0121

GnomAD4 genome AF: 0.00825 AC: 1257 AN: 152310 Hom.: 11 Cov.: 32 AF XY: 0.00808 AC XY: 602 AN XY: 74470

Gnomad4 AFR AF: 0.00236

Gnomad4 AMR AF: 0.0104

Gnomad4 ASJ AF: 0.0205

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0160

Gnomad4 FIN AF: 0.00254

Gnomad4 NFE AF: 0.0116

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.0103 Hom.: 1

Bravo AF: 0.00818

Asia WGS AF: 0.00664 AC: 24 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
Cadd	Benign	14
Dann	Benign	0.77
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000057
dbscSNV1_RF	Benign	0.0040
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: rs41289333; hg19: chr10-17702545;