6-169217827-T-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP2 BP4_Strong BP6_Moderate BS2

The NM_003247.5(THBS2):c.3514A>G(p.Ile1172Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000783 in 1,571,472 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000063 (1 hom.)
• Consequence: THBS2 NM_003247.5 missense, splice_region
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0210

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 -9 ACMG points.

• PP2: Missense variant where missense usually causes diseases, THBS2
• BP4: Computational evidence support a benign effect (MetaRNN=0.033465803).
• BP6: Variant 6-169217827-T-C is Benign according to our data. Variant chr6-169217827-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 2396795.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 30 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
THBS2	NM_003247.5	c.3514A>G	p.Ile1172Val	missense_variant, splice_region_variant	22/22	ENST00000617924.6
THBS2-AS1	NR_134621.1	n.681+3340T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
THBS2	ENST00000617924.6	c.3514A>G	p.Ile1172Val	missense_variant, splice_region_variant	22/22	1	NM_003247.5	P4
THBS2-AS1	ENST00000660724.1	n.639+3340T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000269 AC: 30 AN: 111616 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000874

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000493

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00472

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000669

GnomAD3 exomes AF: 0.0000577 AC: 13 AN: 225440 Hom.: 0 AF XY: 0.0000406 AC XY: 5 AN XY: 123248

Gnomad AFR exome AF: 0.000577

Gnomad AMR exome AF: 0.0000678

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000368

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000977

Gnomad OTH exome AF: 0.000184

GnomAD4 exome AF: 0.0000630 AC: 92 AN: 1459780 Hom.: 1 Cov.: 31 AF XY: 0.0000606 AC XY: 44 AN XY: 726098

Gnomad4 AFR exome AF: 0.00132

Gnomad4 AMR exome AF: 0.0000674

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000233

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.000464

GnomAD4 genome AF: 0.000278 AC: 31 AN: 111692 Hom.: 0 Cov.: 34 AF XY: 0.000316 AC XY: 17 AN XY: 53846

Gnomad4 AFR AF: 0.000910

Gnomad4 AMR AF: 0.000491

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000661

Alfa AF: 0.0000658 Hom.: 0

Bravo AF: 0.000257

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000579 AC: 7

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 12, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	0.66
Dann	Benign	0.71
DEOGEN2	Uncertain	0.44	T;.;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.015	N
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.033	T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.34	N;.;N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	0.45	N;.;.
REVEL	Benign	0.19
Sift	Benign	1.0	T;.;.
Sift4G	Benign	1.0	T;.;T
Polyphen		0.0	B;.;B
Vest4		0.024
MVP		0.32
MPC		0.42
ClinPred		0.0025	T
GERP RS		2.9
Varity_R		0.036
gMVP		0.18

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

LitVar

Other links and lift over

dbSNP: rs113625243; hg19: chr6-169617922;