11-2304184-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_139022.3(TSPAN32):c.259G>T(p.Ala87Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000115 in 1,581,214 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: TSPAN32 NM_139022.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.58

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.031062722).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSPAN32	NM_139022.3	c.259G>T	p.Ala87Ser	missense_variant	3/10	ENST00000182290.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSPAN32	ENST00000182290.9	c.259G>T	p.Ala87Ser	missense_variant	3/10	1	NM_139022.3	P2

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 151840 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000726

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000736

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000244 AC: 48 AN: 196474 Hom.: 0 AF XY: 0.000208 AC XY: 22 AN XY: 105694

Gnomad AFR exome AF: 0.0000828

Gnomad AMR exome AF: 0.000251

Gnomad ASJ exome AF: 0.00356

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000943

Gnomad OTH exome AF: 0.000199

GnomAD4 exome AF: 0.000109 AC: 156 AN: 1429256 Hom.: 0 Cov.: 31 AF XY: 0.000119 AC XY: 84 AN XY: 708316

Gnomad4 AFR exome AF: 0.0000305

Gnomad4 AMR exome AF: 0.000204

Gnomad4 ASJ exome AF: 0.00332

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000429

Gnomad4 OTH exome AF: 0.000270

GnomAD4 genome AF: 0.000171 AC: 26 AN: 151958 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74296

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000736

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000260 Hom.: 0

Bravo AF: 0.000196

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000108 AC: 13

Asia WGS AF: 0.00115 AC: 4 AN: 3478

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

Mar 28, 2023

The c.259G>T (p.A87S) alteration is located in exon 3 (coding exon 3) of the TSPAN32 gene. This alteration results from a G to T substitution at nucleotide position 259, causing the alanine (A) at amino acid position 87 to be replaced by a serine (S). 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	0.11
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.10
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Benign	0.081	T;T;.;.;T
Eigen	Benign	0.061
Eigen_PC	Benign	-0.0065
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.76	T;T;T;T;.
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.031	T;T;T;T;T
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Benign	1.3	L;.;L;.;.
MutationTaster	Benign	0.56	D;D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.53	N;.;N;N;N
REVEL	Uncertain	0.44
Sift	Benign	0.39	T;.;T;T;T
Sift4G	Benign	0.24	T;T;T;T;T
Polyphen		1.0	D;D;D;.;D
Vest4		0.40
MVP		0.76
MPC		0.25
ClinPred		0.10	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.31

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: rs200624662; hg19: chr11-2325414;