rs878853243

Positions:

• chr7-120806619-C-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_012338.4(TSPAN12):​c.542G>T​(p.Cys181Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TSPAN12 NM_012338.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 7.52

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a topological_domain Extracellular (size 113) in uniprot entity TSN12_HUMAN there are 21 pathogenic changes around while only 2 benign (91%) in NM_012338.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.975
• PP5: Variant 7-120806619-C-A is Pathogenic according to our data. Variant chr7-120806619-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 236067.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-120806619-C-A is described in Lovd as [Likely_pathogenic]. Variant chr7-120806619-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSPAN12	NM_012338.4	c.542G>T	p.Cys181Phe	missense_variant	7/8	ENST00000222747.8	NP_036470.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSPAN12	ENST00000222747.8	c.542G>T	p.Cys181Phe	missense_variant	7/8	1	NM_012338.4	ENSP00000222747.3
TSPAN12	ENST00000415871.5	c.542G>T	p.Cys181Phe	missense_variant	8/9	5		ENSP00000397699.1
TSPAN12	ENST00000450414.5	n.*392G>T		non_coding_transcript_exon_variant	5/6	5		ENSP00000397411.1
TSPAN12	ENST00000450414.5	n.*392G>T		3_prime_UTR_variant	5/6	5		ENSP00000397411.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Exudative vitreoretinopathy 5 Pathogenic:2

Pathogenic, criteria provided, single submitter	not provided	Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin	-	- -
Pathogenic, criteria provided, single submitter	research	Erez Levanon lab, Bar Ilan University	May 01, 2016	- -

Persistent hyperplastic primary vitreous, autosomal recessive Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Erez Levanon lab, Bar Ilan University

May 01, 2016

- -

Familial exudative vitreoretinopathy Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Sharon lab, Hadassah-Hebrew University Medical Center

Jun 23, 2019

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 16, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25250762, 26306921, 30452590, 31456290) -

Atrophia bulborum hereditaria Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Erez Levanon lab, Bar Ilan University

May 01, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.89	D;D
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.87	.;D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Pathogenic	3.1	M;M
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-11	D;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.99
MutPred		0.80		Loss of catalytic residue at C181 (P = 0.0547);Loss of catalytic residue at C181 (P = 0.0547);
MVP		0.83
MPC		0.68
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.98
gMVP		0.99

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: rs878853243; hg19: chr7-120446673;