7-120788801-C-T

Variant names:

• chr7-120788801-C-T
• rs267607154
• NM_012338.4:c.709G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_012338.4(TSPAN12):​c.709G>A​(p.Ala237Thr) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A237P) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TSPAN12 NM_012338.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.38
• Publications: 8 publications found

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 Gene-Disease associations (from GenCC):

• exudative vitreoretinopathy 5

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• TSPAN12-related vitreoretinopathy

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
• exudative vitreoretinopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-120788801-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 319.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.895

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSPAN12	NM_012338.4	c.709G>A	p.Ala237Thr	missense_variant	Exon 8 of 8	ENST00000222747.8	NP_036470.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSPAN12	ENST00000222747.8	c.709G>A	p.Ala237Thr	missense_variant	Exon 8 of 8	1	NM_012338.4	ENSP00000222747.3
TSPAN12	ENST00000415871.5	c.709G>A	p.Ala237Thr	missense_variant	Exon 9 of 9	5		ENSP00000397699.1
TSPAN12	ENST00000450414.5	n.*559G>A		non_coding_transcript_exon_variant	Exon 6 of 6	5		ENSP00000397411.1
TSPAN12	ENST00000450414.5	n.*559G>A		3_prime_UTR_variant	Exon 6 of 6	5		ENSP00000397411.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.42	T;T
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	.;D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Uncertain	0.36	D
MutationAssessor	Benign	1.9	L;L
PhyloP100		7.4
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-2.2	N;N
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.018	D;D
Polyphen		1.0	D;D
Vest4		0.78
MutPred		0.75		Loss of stability (P = 0.0549);Loss of stability (P = 0.0549);
MVP		0.63
MPC		0.54
ClinPred		0.88	D
GERP RS		5.7
Varity_R		0.65
gMVP		0.81
Mutation Taster		=40/60	disease causing

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

Other links and lift over

dbSNP: rs267607154; hg19: chr7-120428855; COSMIC: COSV56081767;