rs1866389

Positions:

• chr5-80065442-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003248.6(THBS4):​c.1159G>C​(p.Ala387Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.207 in 1,612,566 control chromosomes in the GnomAD database, including 36,494 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict 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 0.17 (2513 hom., cov: 32)
  • Exomes 𝑓: 0.21 (33981 hom.)
• Consequence: THBS4 NM_003248.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.01

Genes affected

THBS4 (HGNC:11788): (thrombospondin 4) The protein encoded by this gene belongs to the thrombospondin protein family. Thrombospondin family members are adhesive glycoproteins that mediate cell-to-cell and cell-to-matrix interactions. This protein forms a pentamer and can bind to heparin and calcium. It is involved in local signaling in the developing and adult nervous system, and it contributes to spinal sensitization and neuropathic pain states. This gene is activated during the stromal response to invasive breast cancer. It may also play a role in inflammatory responses in Alzheimer's disease. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2015]

THBS4-AS1 (HGNC:40583): (THBS4 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0055117905).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.222 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
THBS4	NM_003248.6	c.1159G>C	p.Ala387Pro	missense_variant	9/22	ENST00000350881.6	NP_003239.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
THBS4	ENST00000350881.6	c.1159G>C	p.Ala387Pro	missense_variant	9/22	1	NM_003248.6	ENSP00000339730	P1
THBS4-AS1	ENST00000503007.5	n.428+3072C>G		intron_variant, non_coding_transcript_variant		3
THBS4	ENST00000511733.1	c.886G>C	p.Ala296Pro	missense_variant	9/22	2		ENSP00000422298
THBS4-AS1	ENST00000661210.1	n.2794C>G		non_coding_transcript_exon_variant	3/3

Frequencies

GnomAD3 genomes AF: 0.171 AC: 25955 AN: 152094 Hom.: 2508 Cov.: 32

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.234

Gnomad AMR AF: 0.150

Gnomad ASJ AF: 0.188

Gnomad EAS AF: 0.0496

Gnomad SAS AF: 0.177

Gnomad FIN AF: 0.165

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.225

Gnomad OTH AF: 0.187

GnomAD3 exomes AF: 0.173 AC: 43428 AN: 250482 Hom.: 4352 AF XY: 0.180 AC XY: 24364 AN XY: 135426

Gnomad AFR exome AF: 0.101

Gnomad AMR exome AF: 0.106

Gnomad ASJ exome AF: 0.182

Gnomad EAS exome AF: 0.0399

Gnomad SAS exome AF: 0.189

Gnomad FIN exome AF: 0.165

Gnomad NFE exome AF: 0.221

Gnomad OTH exome AF: 0.203

GnomAD4 exome AF: 0.210 AC: 307178 AN: 1460354 Hom.: 33981 Cov.: 32 AF XY: 0.210 AC XY: 152425 AN XY: 726552

Gnomad4 AFR exome AF: 0.0960

Gnomad4 AMR exome AF: 0.113

Gnomad4 ASJ exome AF: 0.184

Gnomad4 EAS exome AF: 0.0589

Gnomad4 SAS exome AF: 0.185

Gnomad4 FIN exome AF: 0.170

Gnomad4 NFE exome AF: 0.228

Gnomad4 OTH exome AF: 0.197

GnomAD4 genome AF: 0.171 AC: 25971 AN: 152212 Hom.: 2513 Cov.: 32 AF XY: 0.167 AC XY: 12423 AN XY: 74424

Gnomad4 AFR AF: 0.101

Gnomad4 AMR AF: 0.150

Gnomad4 ASJ AF: 0.188

Gnomad4 EAS AF: 0.0496

Gnomad4 SAS AF: 0.178

Gnomad4 FIN AF: 0.165

Gnomad4 NFE AF: 0.225

Gnomad4 OTH AF: 0.184

Alfa AF: 0.208 Hom.: 2677

Bravo AF: 0.166

TwinsUK AF: 0.232 AC: 859

ALSPAC AF: 0.237 AC: 915

ESP6500AA AF: 0.0994 AC: 438

ESP6500EA AF: 0.221 AC: 1903

ExAC AF: 0.178 AC: 21647

Asia WGS AF: 0.114 AC: 400 AN: 3478

EpiCase AF: 0.212

EpiControl AF: 0.218

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.42	T;.
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.78	T;T
MetaRNN	Benign	0.0055	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-1.2	N;.
MutationTaster	Benign	0.11	P;P
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-2.1	N;N
REVEL	Uncertain	0.30
Sift	Uncertain	0.013	D;D
Sift4G	Benign	0.10	T;T
Polyphen		0.57	P;.
Vest4		0.39
MPC		0.88
ClinPred		0.015	T
GERP RS		5.2
Varity_R		0.46
gMVP		0.64

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

LitVar

Other links and lift over

dbSNP: rs1866389; hg19: chr5-79361265; COSMIC: COSV63469079; COSMIC: COSV63469079;