chr1-155195869-C-T

Position:

• chr1-155195869-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_007112.5(THBS3):​c.2843G>A​(p.Arg948Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R948W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: THBS3 NM_007112.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.91

Genes affected

THBS3 (HGNC:11787): (thrombospondin 3) The protein encoded by this gene belongs to the thrombospondin family. Thrombospondin family members are adhesive glycoproteins that mediate cell-to-cell and cell-to-matrix interactions. This protein forms a pentameric molecule linked by a single disulfide bond. This gene shares a common promoter with metaxin 1. Alternate splicing results in coding and non-coding transcript variants. [provided by RefSeq, Nov 2011]

THBS3-AS1 (HGNC:40582): (THBS3 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12337148).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
THBS3	NM_007112.5	c.2843G>A	p.Arg948Gln	missense_variant	23/23	ENST00000368378.7
THBS3-AS1	NR_183238.1	n.376+497C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
THBS3	ENST00000368378.7	c.2843G>A	p.Arg948Gln	missense_variant	23/23	1	NM_007112.5	P3
THBS3-AS1	ENST00000685687.1	n.372+501C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461824 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727212

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 27, 2022

The c.2843G>A (p.R948Q) alteration is located in exon 23 (coding exon 23) of the THBS3 gene. This alteration results from a G to A substitution at nucleotide position 2843, causing the arginine (R) at amino acid position 948 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	23
DANN	Benign	0.88
DEOGEN2	Benign	0.076	T;.;.;.
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.020
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.91	D;D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.12	T;T;T;T
MetaSVM	Uncertain	0.32	D
MutationAssessor	Benign	0.79	N;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.28	N;.;N;N
REVEL	Uncertain	0.33
Sift	Benign	0.80	T;.;T;T
Sift4G	Benign	0.73	T;T;T;T
Polyphen		0.26	B;.;.;.
Vest4		0.23
MutPred		0.35		Gain of disorder (P = 0.1819);.;.;.;
MVP		0.68
MPC		0.43
ClinPred		0.77	D
GERP RS		4.7
Varity_R		0.18
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-155165660;