rs1554403626

Variant names:

• chr7-120838843-G-GAAACAGC
• rs1554403626
• NM_012338.4:c.212_218dupGCTGTTT

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_012338.4(TSPAN12):​c.212_218dupGCTGTTT​(p.Phe73LeufsTer46) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TSPAN12 NM_012338.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.94
• Publications: 0 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: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-120838843-G-GAAACAGC is Pathogenic according to our data. Variant chr7-120838843-G-GAAACAGC is described in ClinVar as Pathogenic. ClinVar VariationId is 321.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012338.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSPAN12	NM_012338.4	MANE Select	c.212_218dupGCTGTTT	p.Phe73LeufsTer46	frameshift	Exon 4 of 8	NP_036470.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSPAN12	ENST00000222747.8	TSL:1 MANE Select	c.212_218dupGCTGTTT	p.Phe73LeufsTer46	frameshift	Exon 4 of 8	ENSP00000222747.3
	TSPAN12	ENST00000415871.5	TSL:5	c.212_218dupGCTGTTT	p.Phe73LeufsTer46	frameshift	Exon 5 of 9	ENSP00000397699.1
	TSPAN12	ENST00000854320.1		c.212_218dupGCTGTTT	p.Phe73LeufsTer46	frameshift	Exon 5 of 9	ENSP00000524379.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Exudative vitreoretinopathy 5 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.9
Mutation Taster		=3/197	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1554403626; hg19: chr7-120478897;