chr12-71139812-C-T

Position:

• chr12-71139812-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004616.3(TSPAN8):​c.160G>A​(p.Val54Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00247 in 1,613,540 control chromosomes in the GnomAD database, including 102 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (54 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (48 hom.)
• Consequence: TSPAN8 NM_004616.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.12

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0035257936).
• BP6: Variant 12-71139812-C-T is Benign according to our data. Variant chr12-71139812-C-T is described in ClinVar as [Benign]. Clinvar id is 710174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.013 (1976/152234) while in subpopulation AFR AF= 0.0448 (1859/41528). AF 95% confidence interval is 0.0431. There are 54 homozygotes in gnomad4. There are 919 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 54 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSPAN8	NM_004616.3	c.160G>A	p.Val54Ile	missense_variant	4/9	ENST00000247829.8
TSPAN8	NM_001369760.1	c.160G>A	p.Val54Ile	missense_variant	3/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSPAN8	ENST00000247829.8	c.160G>A	p.Val54Ile	missense_variant	4/9	1	NM_004616.3	P1
TSPAN8	ENST00000393330.6	c.160G>A	p.Val54Ile	missense_variant	7/12	1		P1
TSPAN8	ENST00000546561.2	c.160G>A	p.Val54Ile	missense_variant	3/8	1		P1
TSPAN8	ENST00000552786.1			downstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.0130 AC: 1974 AN: 152116 Hom.: 53 Cov.: 33

Gnomad AFR AF: 0.0448

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00452

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00354 AC: 888 AN: 250826 Hom.: 27 AF XY: 0.00255 AC XY: 345 AN XY: 135554

Gnomad AFR exome AF: 0.0477

Gnomad AMR exome AF: 0.00237

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000185

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00138 AC: 2010 AN: 1461306 Hom.: 48 Cov.: 32 AF XY: 0.00114 AC XY: 831 AN XY: 726974

Gnomad4 AFR exome AF: 0.0465

Gnomad4 AMR exome AF: 0.00228

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000144

Gnomad4 OTH exome AF: 0.00278

GnomAD4 genome AF: 0.0130 AC: 1976 AN: 152234 Hom.: 54 Cov.: 33 AF XY: 0.0123 AC XY: 919 AN XY: 74434

Gnomad4 AFR AF: 0.0448

Gnomad4 AMR AF: 0.00451

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00294 Hom.: 12

Bravo AF: 0.0144

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0447 AC: 197

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00447 AC: 543

Asia WGS AF: 0.00202 AC: 7 AN: 3478

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	Jun 14, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.0030
DANN	Benign	0.49
DEOGEN2	Benign	0.024	T;T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0075	N
LIST_S2	Benign	0.28	.;.;T
MetaRNN	Benign	0.0035	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.25	N;N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.30	N;N;N
REVEL	Benign	0.19
Sift	Benign	0.47	T;T;T
Sift4G	Benign	0.52	T;T;T
Polyphen		0.0050	B;B;B
Vest4		0.035
MVP		0.23
MPC		0.071
ClinPred		0.0024	T
GERP RS		-1.9
Varity_R		0.033
gMVP		0.16

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: rs76495455; hg19: chr12-71533592;