11-2304175-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_139022.3(TSPAN32):c.250G>A(p.Val84Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000763 in 1,585,736 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000077 (0 hom.)
• Consequence: TSPAN32 NM_139022.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0810

Genes affected

TSPAN32 (HGNC:13410): (tetraspanin 32) This gene, which is a member of the tetraspanin superfamily, is one of several tumor-suppressing subtransferable fragments located in the imprinted gene domain of chromosome 11p15.5, an important tumor-suppressor gene region. Alterations in this region have been associated with Beckwith-Wiedemann syndrome, Wilms tumor, rhabdomyosarcoma, adrenocortical carcinoma, and lung, ovarian and breast cancers. This gene is located among several imprinted genes; however, this gene, as well as the tumor-suppressing subchromosomal transferable fragment 4, escapes imprinting. This gene may play a role in malignancies and diseases that involve this region, and it is also involved in hematopoietic cell function. Alternatively spliced transcript variants have been described, but their biological validity has not been determined. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15894341).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSPAN32	NM_139022.3	c.250G>A	p.Val84Met	missense_variant	3/10	ENST00000182290.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSPAN32	ENST00000182290.9	c.250G>A	p.Val84Met	missense_variant	3/10	1	NM_139022.3	P2

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152078 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000836 AC: 17 AN: 203262 Hom.: 0 AF XY: 0.000101 AC XY: 11 AN XY: 109418

Gnomad AFR exome AF: 0.0000805

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000664

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000102

Gnomad OTH exome AF: 0.000193

GnomAD4 exome AF: 0.0000767 AC: 110 AN: 1433540 Hom.: 0 Cov.: 31 AF XY: 0.0000676 AC XY: 48 AN XY: 710572

Gnomad4 AFR exome AF: 0.0000607

Gnomad4 AMR exome AF: 0.0000999

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000156

Gnomad4 SAS exome AF: 0.0000122

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000847

Gnomad4 OTH exome AF: 0.0000505

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152196 Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4 AN XY: 74428

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000300 Hom.: 0

Bravo AF: 0.0000793

ExAC AF: 0.0000747 AC: 9

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 01, 2022

The c.250G>A (p.V84M) alteration is located in exon 3 (coding exon 3) of the TSPAN32 gene. This alteration results from a G to A substitution at nucleotide position 250, causing the valine (V) at amino acid position 84 to be replaced by a methionine (M). 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	Benign	0.12
BayesDel_addAF	Uncertain	0.028	T
BayesDel_noAF	Benign	-0.20
Cadd	Benign	16
Dann	Benign	0.96
DEOGEN2	Benign	0.30	T;T;.;.;T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.087	N
LIST_S2	Benign	0.77	T;T;T;T;.
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.16	T;T;T;T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	1.3	L;.;L;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-2.0	N;.;N;N;N
REVEL	Uncertain	0.39
Sift	Benign	0.056	T;.;D;D;D
Sift4G	Benign	0.073	T;T;T;T;T
Polyphen		0.90	P;P;P;.;P
Vest4		0.17
MutPred		0.65		Gain of disorder (P = 0.0578);.;Gain of disorder (P = 0.0578);.;.;
MVP		0.50
MPC		0.052
ClinPred		0.036	T
GERP RS		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.071
gMVP		0.33

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

LitVar

Other links and lift over

dbSNP: rs545681469; hg19: chr11-2325405;