15-39591333-C-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_003246.4(THBS1):c.2396C>A(p.Ala799Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00014 in 1,613,970 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: THBS1 NM_003246.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.65

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 Likely_benign. Variant got -5 ACMG points.

• PP2: Missense variant where missense usually causes diseases, THBS1
• BP4: Computational evidence support a benign effect (MetaRNN=0.16836908).
• BS2: High AC in GnomAd at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
THBS1	NM_003246.4	c.2396C>A	p.Ala799Glu	missense_variant	15/22	ENST00000260356.6
THBS1	XM_047432980.1	c.2396C>A	p.Ala799Glu	missense_variant	15/22
THBS1	XM_011521971.3	c.2222C>A	p.Ala741Glu	missense_variant	14/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
THBS1	ENST00000260356.6	c.2396C>A	p.Ala799Glu	missense_variant	15/22	1	NM_003246.4	P1
THBS1	ENST00000560894.1	n.406C>A		non_coding_transcript_exon_variant	1/2	2
FSIP1	ENST00000642527.1	c.*214+2722G>T		intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152202 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000678 AC: 17 AN: 250816 Hom.: 0 AF XY: 0.0000812 AC XY: 11 AN XY: 135518

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000124

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000149 AC: 218 AN: 1461650 Hom.: 0 Cov.: 31 AF XY: 0.000142 AC XY: 103 AN XY: 727114

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000183

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152320 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74480

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000955 Hom.: 0

Bravo AF: 0.0000756

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000659 AC: 8

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

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

Aug 08, 2023

The c.2396C>A (p.A799E) alteration is located in exon 15 (coding exon 14) of the THBS1 gene. This alteration results from a C to A substitution at nucleotide position 2396, causing the alanine (A) at amino acid position 799 to be replaced by a glutamic acid (E). 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	0.17
BayesDel_addAF	Benign	-0.017	T
BayesDel_noAF	Uncertain	-0.060
Cadd	Benign	16
Dann	Benign	0.85
DEOGEN2	Uncertain	0.51	D
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.17	T
MetaSVM	Uncertain	0.30	D
MutationAssessor	Benign	0.090	N
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	0.070	N
REVEL	Uncertain	0.41
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.52	P
Vest4		0.39
MVP		0.86
MPC		0.62
ClinPred		0.055	T
GERP RS		0.44
Varity_R		0.058
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs146772232; hg19: chr15-39883534;