15-39591206-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_003246.4(THBS1):c.2269C>T(p.His757Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: THBS1 NM_003246.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.38

Genes affected

THBS1 (HGNC:11785): (thrombospondin 1) The protein encoded by this gene is a subunit of a disulfide-linked homotrimeric protein. This protein is an adhesive glycoprotein that mediates cell-to-cell and cell-to-matrix interactions. This protein can bind to fibrinogen, fibronectin, laminin, type V collagen and integrins alpha-V/beta-1. This protein has been shown to play roles in platelet aggregation, angiogenesis, and tumorigenesis. [provided by RefSeq, Jul 2008]

FSIP1 (HGNC:21674): (fibrous sheath interacting protein 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, THBS1
• BP4: Computational evidence support a benign effect (MetaRNN=0.33695042).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
THBS1	NM_003246.4	c.2269C>T	p.His757Tyr	missense_variant	15/22	ENST00000260356.6
THBS1	XM_047432980.1	c.2269C>T	p.His757Tyr	missense_variant	15/22
THBS1	XM_011521971.3	c.2095C>T	p.His699Tyr	missense_variant	14/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
THBS1	ENST00000260356.6	c.2269C>T	p.His757Tyr	missense_variant	15/22	1	NM_003246.4	P1
THBS1	ENST00000560894.1	n.279C>T		non_coding_transcript_exon_variant	1/2	2
FSIP1	ENST00000642527.1	c.*215-2632G>A		intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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 24, 2023

The c.2269C>T (p.H757Y) alteration is located in exon 15 (coding exon 14) of the THBS1 gene. This alteration results from a C to T substitution at nucleotide position 2269, causing the histidine (H) at amino acid position 757 to be replaced by a tyrosine (Y). 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	0.073
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
Cadd	Uncertain	25
Dann	Benign	0.97
DEOGEN2	Uncertain	0.53	D
Eigen	Benign	-0.028
Eigen_PC	Benign	0.18
FATHMM_MKL	Benign	0.62	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.34	T
MetaSVM	Uncertain	0.57	D
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	0.93	D
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	0.97	N
REVEL	Uncertain	0.30
Sift	Benign	0.20	T
Sift4G	Benign	0.13	T
Polyphen		0.21	B
Vest4		0.51
MutPred		0.40		Loss of catalytic residue at H757 (P = 0.0533);
MVP		0.37
MPC		0.77
ClinPred		0.45	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.047
gMVP		0.67

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-39883407;