11-2313679-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_139022.3(TSPAN32):c.380A>G(p.Tyr127Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000435 in 1,608,352 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

TSPAN32
NM_139022.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.561

Variant links:

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 links:

LOC124902612 (HGNC:):

LOC124902612 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.807

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSPAN32	NM_139022.3 linkuse as main transcript	c.380A>G	p.Tyr127Cys	missense_variant	5/10	ENST00000182290.9
LOC124902612	XR_007062552.1 linkuse as main transcript	n.223T>C		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSPAN32	ENST00000182290.9 linkuse as main transcript	c.380A>G	p.Tyr127Cys	missense_variant	5/10	1	NM_139022.3	P2	Q96QS1-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000249

AC:

AN:

240930

Hom.:

AF XY:

0.00000767

AC XY:

AN XY:

130382

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000177

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000412

AC:

AN:

1456198

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

723764

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000113

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.01e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152154

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 09, 2021

The c.380A>G (p.Y127C) alteration is located in exon 5 (coding exon 5) of the TSPAN32 gene. This alteration results from a A to G substitution at nucleotide position 380, causing the tyrosine (Y) at amino acid position 127 to be replaced by a cysteine (C). 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

Pathogenic

0.79

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Pathogenic

0.28

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Pathogenic

0.83

D;T;.;.;T

Eigen

Benign

0.077

Eigen_PC

Benign

-0.10

FATHMM_MKL

Benign

0.35

LIST_S2

Uncertain

0.90

D;D;D;D;.

M_CAP

Uncertain

0.22

MetaRNN

Pathogenic

0.81

D;D;D;D;D

MetaSVM

Uncertain

0.66

MutationAssessor

Benign

1.9

L;.;L;.;.

MutationTaster

Benign

0.82

D;D;D;D

PrimateAI

Uncertain

0.50

PROVEAN

Pathogenic

-6.8

D;.;D;D;D

REVEL

Pathogenic

0.69

Sift

Pathogenic

0.0

D;.;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D

Polyphen

1.0

D;D;D;.;D

Vest4

0.66

MutPred

0.68

Loss of phosphorylation at Y127 (P = 0.0176);.;Loss of phosphorylation at Y127 (P = 0.0176);.;.;

MVP

0.86

MPC

0.29

ClinPred

0.90

GERP RS

3.8

Varity_R

0.63

gMVP

0.96

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over