chr11-2316248-G-A

Position:

• chr11-2316248-G-A

Variant summary

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

The NM_139022.3(TSPAN32):​c.563G>A​(p.Arg188Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000207 in 1,597,560 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 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: 33)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: TSPAN32 NM_139022.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.413

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]

TSPAN32 (HGNC:):

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=0.033928245).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSPAN32	NM_139022.3	c.563G>A	p.Arg188Gln	missense_variant	7/10	ENST00000182290.9	NP_620591.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSPAN32	ENST00000182290.9	c.563G>A	p.Arg188Gln	missense_variant	7/10	1	NM_139022.3	ENSP00000182290.5

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152210 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000176 AC: 40 AN: 227238 Hom.: 0 AF XY: 0.000163 AC XY: 20 AN XY: 122966

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000920

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000724

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000341

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000211 AC: 305 AN: 1445232 Hom.: 0 Cov.: 34 AF XY: 0.000206 AC XY: 148 AN XY: 717754

Gnomad4 AFR exome AF: 0.0000902

Gnomad4 AMR exome AF: 0.0000928

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000256

Gnomad4 SAS exome AF: 0.0000838

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000255

Gnomad4 OTH exome AF: 0.000134

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152328 Hom.: 0 Cov.: 33 AF XY: 0.000175 AC XY: 13 AN XY: 74492

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000288 Hom.: 0

Bravo AF: 0.000166

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.000223 AC: 27

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.563G>A (p.R188Q) alteration is located in exon 7 (coding exon 7) of the TSPAN32 gene. This alteration results from a G to A substitution at nucleotide position 563, causing the arginine (R) at amino acid position 188 to be replaced by a glutamine (Q). 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	0.080
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Benign	0.14	T;T;.;.;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.66	T;T;T;T;.
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.034	T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.55	N;.;N;.;.
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.42	N;.;N;N;N
REVEL	Benign	0.14
Sift	Benign	0.21	T;.;T;T;T
Sift4G	Benign	0.22	T;T;T;T;T
Polyphen		0.50	P;P;B;.;P
Vest4		0.17
MVP		0.47
MPC		0.047
ClinPred		0.020	T
GERP RS		-1.8
Varity_R		0.039
gMVP		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs766761476; hg19: chr11-2337478; COSMIC: COSV51722806; COSMIC: COSV51722806;