rs2228262

chr15-39589977-A-G

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. PP2 BP4_Strong BA1

The NM_003246.4(THBS1):c.2099A>G(p.Asn700Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.104 in 1,613,160 control chromosomes in the GnomAD database, including 9,683 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.079 (651 hom., cov: 32)
  • Exomes 𝑓: 0.11 (9032 hom.)
• Consequence: THBS1 NM_003246.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.32

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 Benign. Variant got -11 ACMG points.

• PP2: Missense variant where missense usually causes diseases, THBS1
• BP4: Computational evidence support a benign effect (MetaRNN=0.0038629174).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.117 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
THBS1	NM_003246.4	c.2099A>G	p.Asn700Ser	missense_variant	13/22	ENST00000260356.6
THBS1	XM_047432980.1	c.2099A>G	p.Asn700Ser	missense_variant	13/22
THBS1	XM_011521971.3	c.1925A>G	p.Asn642Ser	missense_variant	12/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
THBS1	ENST00000260356.6	c.2099A>G	p.Asn700Ser	missense_variant	13/22	1	NM_003246.4	P1
FSIP1	ENST00000642527.1	c.*215-1403T>C		intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0795 AC: 12093 AN: 152198 Hom.: 652 Cov.: 32

Gnomad AFR AF: 0.0301

Gnomad AMI AF: 0.0888

Gnomad AMR AF: 0.0627

Gnomad ASJ AF: 0.0582

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0520

Gnomad FIN AF: 0.0974

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.120

Gnomad OTH AF: 0.0780

GnomAD3 exomes AF: 0.0793 AC: 19725 AN: 248600 Hom.: 1029 AF XY: 0.0814 AC XY: 10929 AN XY: 134308

Gnomad AFR exome AF: 0.0301

Gnomad AMR exome AF: 0.0417

Gnomad ASJ exome AF: 0.0592

Gnomad EAS exome AF: 0.000491

Gnomad SAS exome AF: 0.0497

Gnomad FIN exome AF: 0.0982

Gnomad NFE exome AF: 0.117

Gnomad OTH exome AF: 0.0806

GnomAD4 exome AF: 0.106 AC: 155200 AN: 1460844 Hom.: 9032 Cov.: 32 AF XY: 0.105 AC XY: 76082 AN XY: 726602

Gnomad4 AFR exome AF: 0.0253

Gnomad4 AMR exome AF: 0.0446

Gnomad4 ASJ exome AF: 0.0572

Gnomad4 EAS exome AF: 0.000277

Gnomad4 SAS exome AF: 0.0523

Gnomad4 FIN exome AF: 0.101

Gnomad4 NFE exome AF: 0.122

Gnomad4 OTH exome AF: 0.0914

GnomAD4 genome AF: 0.0794 AC: 12088 AN: 152316 Hom.: 651 Cov.: 32 AF XY: 0.0772 AC XY: 5748 AN XY: 74474

Gnomad4 AFR AF: 0.0300

Gnomad4 AMR AF: 0.0626

Gnomad4 ASJ AF: 0.0582

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0516

Gnomad4 FIN AF: 0.0974

Gnomad4 NFE AF: 0.120

Gnomad4 OTH AF: 0.0767

Alfa AF: 0.103 Hom.: 2271

Bravo AF: 0.0734

TwinsUK AF: 0.129 AC: 480

ALSPAC AF: 0.117 AC: 452

ESP6500AA AF: 0.0361 AC: 159

ESP6500EA AF: 0.114 AC: 982

ExAC AF: 0.0808 AC: 9807

Asia WGS AF: 0.0220 AC: 77 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.17
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.67	D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	0.0000085	P
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.56
Sift	Uncertain	0.027	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.29
MPC		1.1
ClinPred		0.027	T
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.16
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs2228262; hg19: chr15-39882178; COSMIC: COSV52950831; COSMIC: COSV52950831;