12-71144171-C-T

Position:

• chr12-71144171-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_004616.3(TSPAN8):​c.103G>A​(p.Val35Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0119 in 1,611,794 control chromosomes in the GnomAD database, including 141 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0097 (11 hom., cov: 32)
  • Exomes 𝑓: 0.012 (130 hom.)
• Consequence: TSPAN8 NM_004616.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.701

Genes affected

TSPAN8 (HGNC:11855): (tetraspanin 8) 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. This encoded protein is a cell surface glycoprotein that is known to complex with integrins. This gene is expressed in different carcinomas. The use of alternate polyadenylation sites has been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008988857).
• BP6: Variant 12-71144171-C-T is Benign according to our data. Variant chr12-71144171-C-T is described in ClinVar as [Benign]. Clinvar id is 710022.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSPAN8	NM_004616.3	c.103G>A	p.Val35Ile	missense_variant	3/9	ENST00000247829.8
TSPAN8	NM_001369760.1	c.103G>A	p.Val35Ile	missense_variant	2/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSPAN8	ENST00000247829.8	c.103G>A	p.Val35Ile	missense_variant	3/9	1	NM_004616.3	P1
TSPAN8	ENST00000393330.6	c.103G>A	p.Val35Ile	missense_variant	6/12	1		P1
TSPAN8	ENST00000546561.2	c.103G>A	p.Val35Ile	missense_variant	2/8	1		P1
TSPAN8	ENST00000552786.1	n.362G>A		non_coding_transcript_exon_variant	4/5	5

Frequencies

GnomAD3 genomes AF: 0.00971 AC: 1476 AN: 152032 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00215

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00685

Gnomad FIN AF: 0.0321

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0139

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00944 AC: 2359 AN: 249804 Hom.: 19 AF XY: 0.00980 AC XY: 1324 AN XY: 135088

Gnomad AFR exome AF: 0.00160

Gnomad AMR exome AF: 0.00279

Gnomad ASJ exome AF: 0.00528

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00595

Gnomad FIN exome AF: 0.0277

Gnomad NFE exome AF: 0.0121

Gnomad OTH exome AF: 0.00854

GnomAD4 exome AF: 0.0121 AC: 17709 AN: 1459644 Hom.: 130 Cov.: 30 AF XY: 0.0120 AC XY: 8711 AN XY: 726158

Gnomad4 AFR exome AF: 0.00185

Gnomad4 AMR exome AF: 0.00282

Gnomad4 ASJ exome AF: 0.00460

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00618

Gnomad4 FIN exome AF: 0.0266

Gnomad4 NFE exome AF: 0.0134

Gnomad4 OTH exome AF: 0.00982

GnomAD4 genome AF: 0.00969 AC: 1475 AN: 152150 Hom.: 11 Cov.: 32 AF XY: 0.0102 AC XY: 758 AN XY: 74348

Gnomad4 AFR AF: 0.00214

Gnomad4 AMR AF: 0.00236

Gnomad4 ASJ AF: 0.00634

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00685

Gnomad4 FIN AF: 0.0321

Gnomad4 NFE AF: 0.0139

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.0111 Hom.: 15

Bravo AF: 0.00698

TwinsUK AF: 0.0154 AC: 57

ALSPAC AF: 0.0145 AC: 56

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.0133 AC: 114

ExAC AF: 0.00929 AC: 1128

Asia WGS AF: 0.00144 AC: 5 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 25, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.034	T;T;T
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.64	.;.;T
MetaRNN	Benign	0.0090	T;T;T
MetaSVM	Benign	-0.68	T
MutationAssessor	Uncertain	2.5	M;M;M
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.50	N;N;N
REVEL	Benign	0.27
Sift	Benign	0.12	T;T;T
Sift4G	Benign	0.12	T;T;T
Polyphen		0.79	P;P;P
Vest4		0.041
MVP		0.67
MPC		0.26
ClinPred		0.047	T
GERP RS		2.0
Varity_R		0.12
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs17849952; hg19: chr12-71537951;