chr6-169217827-T-C

Variant names:

• chr6-169217827-T-C
• rs113625243
• NM_003247.5:c.3514A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. 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. 17/22 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
• Publications: 1 publications found

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

Our verdict: Benign. The variant received -10 ACMG points.

• 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 VariationId is 2396795.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 31 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003247.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THBS2	NM_003247.5	MANE Select	c.3514A>G	p.Ile1172Val	missense splice_region	Exon 22 of 22	NP_003238.2
	THBS2	NM_001381939.1		c.3340A>G	p.Ile1114Val	missense splice_region	Exon 21 of 21	NP_001368868.1	A0A7I2V585
	THBS2	NM_001381942.1		c.3283A>G	p.Ile1095Val	missense splice_region	Exon 22 of 22	NP_001368871.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THBS2	ENST00000617924.6	TSL:1 MANE Select	c.3514A>G	p.Ile1172Val	missense splice_region	Exon 22 of 22	ENSP00000482784.1	P35442
	THBS2	ENST00000366787.7	TSL:1	c.3514A>G	p.Ile1172Val	missense splice_region	Exon 23 of 23	ENSP00000355751.3	P35442
	THBS2	ENST00000649844.1		c.3529A>G	p.Ile1177Val	missense splice_region	Exon 22 of 22	ENSP00000497834.1	A0A3B3ITK0

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

GnomAD2 exomes AF: 0.0000577 AC: 13 AN: 225440 AF XY: 0.0000406

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 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

African (AFR) AF: 0.00132 AC: 44 AN: 33406

American (AMR) AF: 0.0000674 AC: 3 AN: 44522

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26092

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.0000233 AC: 2 AN: 85894

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52740

Middle Eastern (MID) AF: 0.00159 AC: 9 AN: 5678

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111452

Other (OTH) AF: 0.000464 AC: 28 AN: 60310

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

African (AFR) AF: 0.000910 AC: 24 AN: 26384

American (AMR) AF: 0.000491 AC: 5 AN: 10178

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2796

East Asian (EAS) AF: 0.00 AC: 0 AN: 4504

South Asian (SAS) AF: 0.00 AC: 0 AN: 3322

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7602

Middle Eastern (MID) AF: 0.00500 AC: 1 AN: 200

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 54472

Other (OTH) AF: 0.000661 AC: 1 AN: 1512

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

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.033	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.021
PrimateAI	Benign	0.43	T
PROVEAN	Benign	0.45	N
REVEL	Benign	0.19
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	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
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs113625243; hg19: chr6-169617922;