chr7-120815787-A-C

Variant names:

• chr7-120815787-A-C
• NM_012338.4:c.302T>G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PM5 PP3_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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.39

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 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	c.302T>G	p.Leu101Arg	missense_variant	Exon 5 of 8	ENST00000222747.8	NP_036470.1
TSPAN12	XM_005250239.4	c.302T>G	p.Leu101Arg	missense_variant	Exon 6 of 9		XP_005250296.1
TSPAN12	XM_047420095.1	c.302T>G	p.Leu101Arg	missense_variant	Exon 6 of 9		XP_047276051.1
TSPAN12	XM_047420096.1	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	c.302T>G	p.Leu101Arg	missense_variant	Exon 5 of 8	1	NM_012338.4	ENSP00000222747.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460638 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726618

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.: 32

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	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D;D;.;.;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	.;D;D;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D
MetaSVM	Uncertain	0.48	D
MutationAssessor	Uncertain	2.9	M;M;.;.;.
PrimateAI	Pathogenic	0.89	D
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	D
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.

Other links and lift over

hg19: chr7-120455841;