11-2313723-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP6_Moderate

The NM_139022.3(TSPAN32):c.424C>T(p.Arg142Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000099 in 1,606,462 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00011 (1 hom.)
• Consequence: TSPAN32 NM_139022.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.52

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]

LOC124902612 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 11-2313723-C-T is Benign according to our data. Variant chr11-2313723-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2404240.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSPAN32	NM_139022.3	c.424C>T	p.Arg142Trp	missense_variant	5/10	ENST00000182290.9
LOC124902612	XR_007062552.1	n.179G>A		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSPAN32	ENST00000182290.9	c.424C>T	p.Arg142Trp	missense_variant	5/10	1	NM_139022.3	P2

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152092 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000772

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000101 AC: 24 AN: 237166 Hom.: 0 AF XY: 0.000101 AC XY: 13 AN XY: 128516

Gnomad AFR exome AF: 0.0000681

Gnomad AMR exome AF: 0.0000299

Gnomad ASJ exome AF: 0.000512

Gnomad EAS exome AF: 0.000452

Gnomad SAS exome AF: 0.0000347

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000743

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000105 AC: 153 AN: 1454250 Hom.: 1 Cov.: 31 AF XY: 0.0000996 AC XY: 72 AN XY: 722798

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000227

Gnomad4 ASJ exome AF: 0.000231

Gnomad4 EAS exome AF: 0.000127

Gnomad4 SAS exome AF: 0.0000236

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000112

Gnomad4 OTH exome AF: 0.000233

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152212 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74396

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000774

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000191 Hom.: 0

Bravo AF: 0.0000680

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000990 AC: 12

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 12, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	0.043
Dann	Benign	0.74
DEOGEN2	Benign	0.35	T;T;.;.;T
Eigen	Benign	-2.8
Eigen_PC	Benign	-2.9
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.47	T;T;T;T;.
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.011	T;T;T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	-0.69	N;.;N;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.34	N;.;N;N;N
REVEL	Benign	0.17
Sift	Benign	0.048	D;.;D;T;D
Sift4G	Uncertain	0.035	D;D;D;D;D
Polyphen		0.0	B;B;B;.;B
Vest4		0.17
MVP		0.44
MPC		0.037
ClinPred		0.035	T
GERP RS		-7.2
Varity_R		0.040
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.22		Position offset: 32

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs374473348; hg19: chr11-2334953; COSMIC: COSV51719850; COSMIC: COSV51719850;