7-120788635-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_012338.4(TSPAN12):c.875T>C(p.Met292Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000409 in 1,614,022 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M292K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

TSPAN12
NM_012338.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 4.24

Variant links:

Genes affected

TSPAN12 (HGNC:21641): (tetraspanin 12) The protein encoded by this gene is a member of the transmembrane 4 superfamily, also known as the tetraspanin family. Most of these members are cell-surface proteins that are characterized by the presence of four hydrophobic domains. The proteins mediate signal transduction events that play a role in the regulation of cell development, activation, growth and motility. [provided by RefSeq, Jul 2008]

TSPAN12 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.10808036).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSPAN12	NM_012338.4 linkuse as main transcript	c.875T>C	p.Met292Thr	missense_variant	8/8	ENST00000222747.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSPAN12	ENST00000222747.8 linkuse as main transcript	c.875T>C	p.Met292Thr	missense_variant	8/8	1	NM_012338.4	P1	O95859-1
TSPAN12	ENST00000415871.5 linkuse as main transcript	c.875T>C	p.Met292Thr	missense_variant	9/9	5		P1	O95859-1
TSPAN12	ENST00000450414.5 linkuse as main transcript	c.*725T>C		3_prime_UTR_variant, NMD_transcript_variant	6/6	5

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000279

AC:

AN:

250870

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135558

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000618

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000397

AC:

AN:

1461842

Hom.:

Cov.:

AF XY:

0.0000454

AC XY:

AN XY:

727220

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.0000522

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000847

Hom.:

Bravo

AF:

0.0000491

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 21, 2023

The c.875T>C (p.M292T) alteration is located in exon 8 (coding exon 7) of the TSPAN12 gene. This alteration results from a T to C substitution at nucleotide position 875, causing the methionine (M) at amino acid position 292 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 12, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 944541). This variant has not been reported in the literature in individuals affected with TSPAN12-related conditions. This variant is present in population databases (rs372498612, gnomAD 0.006%). This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 292 of the TSPAN12 protein (p.Met292Thr). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.34

Cadd

Benign

Dann

Uncertain

0.97

DEOGEN2

Benign

0.072

T;T

Eigen

Benign

-0.22

Eigen_PC

Benign

0.034

FATHMM_MKL

Uncertain

0.86

M_CAP

Benign

0.0083

MetaRNN

Benign

0.11

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.20

N;N

MutationTaster

Benign

0.93

D;D

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-0.25

N;N

REVEL

Benign

0.062

Sift

Benign

0.20

T;T

Sift4G

Benign

0.50

T;T

Polyphen

0.0

B;B

Vest4

0.35

MVP

0.12

MPC

0.13

ClinPred

0.15

GERP RS

5.8

Varity_R

0.087

gMVP

0.50

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