Genetic Variant THBS4:p.Pro28Arg (chr5-80035620-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_003248.6(THBS4):c.83C>G(p.Pro28Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000145 in 1,378,578 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 8.2e-7 ( 0 hom. )

Consequence

THBS4
NM_003248.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.02

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.20833644).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003248.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
THBS4	NM_003248.6	MANE Select	c.83C>G	p.Pro28Arg	missense	Exon 1 of 22	NP_003239.2
THBS4	NM_001306212.2		c.-185-4457C>G		intron	N/A	NP_001293141.1	E7ES19
THBS4	NM_001306213.2		c.-185-4457C>G		intron	N/A	NP_001293142.1	E7ES19

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
THBS4	ENST00000350881.6	TSL:1 MANE Select	c.83C>G	p.Pro28Arg	missense	Exon 1 of 22	ENSP00000339730.2	P35443
THBS4	ENST00000970348.1		c.83C>G	p.Pro28Arg	missense	Exon 1 of 22	ENSP00000640407.1
THBS4	ENST00000854344.1		c.83C>G	p.Pro28Arg	missense	Exon 1 of 22	ENSP00000524403.1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000209

AC:

AN:

47862

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000435

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

8.15e-7

AC:

AN:

1226496

Hom.:

Cov.:

AF XY:

0.00000167

AC XY:

AN XY:

598876

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25550

American (AMR)

AF:

0.00

AC:

AN:

17156

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19126

East Asian (EAS)

AF:

0.0000351

AC:

AN:

28502

South Asian (SAS)

AF:

0.00

AC:

AN:

55092

European-Finnish (FIN)

AF:

0.00

AC:

AN:

30338

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3834

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

997122

Other (OTH)

AF:

0.00

AC:

AN:

49776

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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:

0.00000658

AC:

AN:

152082

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74284

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41460

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.000194

AC:

AN:

5160

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67966

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.00000914

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

-0.050

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

Eigen

Uncertain

0.22

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.66

M_CAP

Uncertain

0.27

MetaRNN

Benign

0.21

MetaSVM

Uncertain

-0.18

MutationAssessor

Benign

1.6

PhyloP100

4.0

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-1.3

REVEL

Uncertain

0.57

Sift

Benign

0.34

Sift4G

Benign

0.61

Polyphen

0.84

Vest4

0.45

MutPred

0.43

Gain of MoRF binding (P = 0.0153)

MVP

0.92

MPC

0.93

ClinPred

0.92

GERP RS

4.1

PromoterAI

0.011

Neutral

(source)

Varity_R

0.14

gMVP

0.28

Mutation Taster

=87/13

polymorphism

(source)

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

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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