dbSNP rs267607152: TSPAN12:p.Leu101Arg (chr7-120815787-A-C) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PM5PP3_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 Likely pathogenic.

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

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 Likely_pathogenic. Variant got 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-120815787-A-T is described in Lovd as [Likely_pathogenic].

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

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:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

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

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;.;.;.

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

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over