Genetic Variant THBS4:c.*574C>A (chr5-80083715-C-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000854343.1(THBS4):c.*574C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.226 in 152,380 control chromosomes in the GnomAD database, including 4,597 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.

Frequency

Genomes: 𝑓 0.23 ( 4595 hom., cov: 33)

Exomes 𝑓: 0.061 ( 2 hom. )

Consequence

THBS4
ENST00000854343.1 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.192

Publications

9 publications found

Variant links:

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 links:

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

THBS4-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.357 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000854343.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THBS4-AS1	NR_109930.1		n.-50G>T		upstream_gene	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
THBS4	ENST00000854343.1		c.*574C>A	3_prime_UTR	Exon 21 of 21	ENSP00000524402.1
THBS4-AS1	ENST00000514042.1	TSL:1	n.-61G>T	upstream_gene	N/A
THBS4-AS1	ENST00000799170.1		n.-50G>T	upstream_gene	N/A

Frequencies

GnomAD3 genomes

AF:

0.226

AC:

34390

AN:

152018

Hom.:

4585

Cov.:

show subpopulations

Gnomad AFR

AF:

0.361

Gnomad AMI

AF:

0.195

Gnomad AMR

AF:

0.243

Gnomad ASJ

AF:

0.181

Gnomad EAS

AF:

0.293

Gnomad SAS

AF:

0.245

Gnomad FIN

AF:

0.208

Gnomad MID

AF:

0.196

Gnomad NFE

AF:

0.140

Gnomad OTH

AF:

0.230

GnomAD4 exome

AF:

0.0615

AC:

AN:

244

Hom.:

AF XY:

0.0797

AC XY:

AN XY:

138

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AF:

0.100

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AF:

0.250

AC:

AN:

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0550

AC:

AN:

200

Other (OTH)

AF:

0.00

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.226

AC:

34438

AN:

152136

Hom.:

4595

Cov.:

AF XY:

0.230

AC XY:

17136

AN XY:

74390

show subpopulations

African (AFR)

AF:

0.361

AC:

14984

AN:

41454

American (AMR)

AF:

0.243

AC:

3718

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.181

AC:

627

AN:

3472

East Asian (EAS)

AF:

0.293

AC:

1518

AN:

5178

South Asian (SAS)

AF:

0.243

AC:

1174

AN:

4826

European-Finnish (FIN)

AF:

0.208

AC:

2199

AN:

10586

Middle Eastern (MID)

AF:

0.204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.140

AC:

9494

AN:

68014

Other (OTH)

AF:

0.231

AC:

487

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1320

2640

3959

5279

6599

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

360

720

1080

1440

1800

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.177

Hom.:

5517

Bravo

AF:

0.237

Asia WGS

AF:

0.316

AC:

1097

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.77

(source)

DANN

Benign

0.26

PhyloP100

-0.19

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over