rs6422747

chr6-169229688-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_003247.5(THBS2):c.2152-9C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.591 in 1,606,948 control chromosomes in the GnomAD database, including 286,323 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.67 (36273 hom., cov: 33)
  • Exomes 𝑓: 0.58 (250050 hom.)
• Consequence: THBS2 NM_003247.5 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00002677
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.431

Genes affected

THBS2 (HGNC:11786): (thrombospondin 2) The protein encoded by this gene belongs to the thrombospondin family. It is a disulfide-linked homotrimeric glycoprotein that mediates cell-to-cell and cell-to-matrix interactions. This protein has been shown to function as a potent inhibitor of tumor growth and angiogenesis. Studies of the mouse counterpart suggest that this protein may modulate the cell surface properties of mesenchymal cells and be involved in cell adhesion and migration. [provided by RefSeq, Jul 2008]

THBS2-AS1 (HGNC:56059): (THBS2 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 6-169229688-G-A is Benign according to our data. Variant chr6-169229688-G-A is described in ClinVar as [Benign]. Clinvar id is 3059455.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.903 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
THBS2	NM_003247.5	c.2152-9C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000617924.6
THBS2-AS1	NR_134621.1	n.682-9537G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
THBS2	ENST00000617924.6	c.2152-9C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_003247.5	P4
THBS2-AS1	ENST00000660724.1	n.640-9537G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.673 AC: 102348 AN: 151970 Hom.: 36203 Cov.: 33

Gnomad AFR AF: 0.910

Gnomad AMI AF: 0.567

Gnomad AMR AF: 0.662

Gnomad ASJ AF: 0.672

Gnomad EAS AF: 0.585

Gnomad SAS AF: 0.601

Gnomad FIN AF: 0.512

Gnomad MID AF: 0.687

Gnomad NFE AF: 0.571

Gnomad OTH AF: 0.665

GnomAD3 exomes AF: 0.612 AC: 153483 AN: 250848 Hom.: 47997 AF XY: 0.604 AC XY: 81915 AN XY: 135552

Gnomad AFR exome AF: 0.917

Gnomad AMR exome AF: 0.661

Gnomad ASJ exome AF: 0.665

Gnomad EAS exome AF: 0.593

Gnomad SAS exome AF: 0.606

Gnomad FIN exome AF: 0.520

Gnomad NFE exome AF: 0.570

Gnomad OTH exome AF: 0.617

GnomAD4 exome AF: 0.583 AC: 847636 AN: 1454860 Hom.: 250050 Cov.: 28 AF XY: 0.582 AC XY: 421732 AN XY: 724158

Gnomad4 AFR exome AF: 0.925

Gnomad4 AMR exome AF: 0.660

Gnomad4 ASJ exome AF: 0.667

Gnomad4 EAS exome AF: 0.558

Gnomad4 SAS exome AF: 0.603

Gnomad4 FIN exome AF: 0.523

Gnomad4 NFE exome AF: 0.567

Gnomad4 OTH exome AF: 0.617

GnomAD4 genome AF: 0.674 AC: 102481 AN: 152088 Hom.: 36273 Cov.: 33 AF XY: 0.670 AC XY: 49827 AN XY: 74334

Gnomad4 AFR AF: 0.910

Gnomad4 AMR AF: 0.662

Gnomad4 ASJ AF: 0.672

Gnomad4 EAS AF: 0.585

Gnomad4 SAS AF: 0.602

Gnomad4 FIN AF: 0.512

Gnomad4 NFE AF: 0.571

Gnomad4 OTH AF: 0.669

Alfa AF: 0.629 Hom.: 13954

Bravo AF: 0.695

Asia WGS AF: 0.665 AC: 2313 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

THBS2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 17, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	0.048
Dann	Benign	0.77

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000027
dbscSNV1_RF	Benign	0.0060
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

LitVar

Other links and lift over

dbSNP: rs6422747; hg19: chr6-169629783; COSMIC: COSV64677774; COSMIC: COSV64677774;