chr6-169223271-T-C

Variant names:

• chr6-169223271-T-C
• NM_003247.5:c.2978A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_003247.5(THBS2):​c.2978A>G​(p.Asn993Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,500 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: THBS2 NM_003247.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.43
• Publications: 0 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.896

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.2978A>G	p.Asn993Ser	missense	Exon 18 of 22	NP_003238.2
	THBS2	NM_001381939.1		c.2804A>G	p.Asn935Ser	missense	Exon 17 of 21	NP_001368868.1	A0A7I2V585
	THBS2	NM_001381942.1		c.2747A>G	p.Asn916Ser	missense	Exon 18 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.2978A>G	p.Asn993Ser	missense	Exon 18 of 22	ENSP00000482784.1	P35442
	THBS2	ENST00000366787.7	TSL:1	c.2978A>G	p.Asn993Ser	missense	Exon 19 of 23	ENSP00000355751.3	P35442
	THBS2	ENST00000649844.1		c.2993A>G	p.Asn998Ser	missense	Exon 18 of 22	ENSP00000497834.1	A0A3B3ITK0

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461500 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726952

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111714

Other (OTH) AF: 0.00 AC: 0 AN: 60378

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

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	Pathogenic	0.83
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		7.4
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.054	T
Polyphen		1.0	D
Vest4		0.83
MutPred		0.75		Gain of disorder (P = 0.055)
MVP		0.97
MPC		1.3
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.84
gMVP		0.71
Mutation Taster		=86/14	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

hg19: chr6-169623366;