dbSNP rs267607152: TSPAN12:p.Leu101Arg (chr7-120815787-A-C) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_012338.4(TSPAN12):c.302T>G(p.Leu101Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,638 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. L101H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TSPAN12
NM_012338.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.39

Publications

0 publications found

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 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

TSPAN12 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.977

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSPAN12	NM_012338.4 link	c.302T>G	p.Leu101Arg	missense_variant	Exon 5 of 8	ENST00000222747.8	NP_036470.1	O95859-1A0A024R740
TSPAN12	XM_005250239.4 link	c.302T>G	p.Leu101Arg	missense_variant	Exon 6 of 9		XP_005250296.1	O95859-1A0A024R740
TSPAN12	XM_047420095.1 link	c.302T>G	p.Leu101Arg	missense_variant	Exon 6 of 9		XP_047276051.1
TSPAN12	XM_047420096.1 link	c.286-5217T>G		intron_variant	Intron 5 of 7		XP_047276052.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSPAN12	ENST00000222747.8 link	c.302T>G	p.Leu101Arg	missense_variant	Exon 5 of 8	1	NM_012338.4	ENSP00000222747.3		O95859-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460638

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726618

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33458

American (AMR)

AF:

0.00

AC:

AN:

44632

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26094

East Asian (EAS)

AF:

0.00

AC:

AN:

39654

South Asian (SAS)

AF:

0.00

AC:

AN:

86178

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52930

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111572

Other (OTH)

AF:

0.00

AC:

AN:

60356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.84

D;D;.;.;.

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.89

.;D;D;D;D

M_CAP

Uncertain

0.16

MetaRNN

Pathogenic

0.98

D;D;D;D;D

MetaSVM

Uncertain

0.48

MutationAssessor

Uncertain

2.9

M;M;.;.;.

PhyloP100

8.4

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-4.5

D;D;D;D;D

REVEL

Pathogenic

0.88

Sift

Uncertain

0.0010

D;D;D;D;D

Sift4G

Uncertain

0.0040

D;D;.;D;.

Polyphen

1.0

D;D;.;.;.

Vest4

0.91

MutPred

0.94

Gain of methylation at L101 (P = 0.0135);Gain of methylation at L101 (P = 0.0135);Gain of methylation at L101 (P = 0.0135);Gain of methylation at L101 (P = 0.0135);Gain of methylation at L101 (P = 0.0135);

MVP

0.91

MPC

0.66

ClinPred

1.0

GERP RS

5.3

Varity_R

0.97

gMVP

0.97

Mutation Taster

=11/89

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over