dbSNP rs443095: THBS4:c.1195-1246G>A (chr5-80066727-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_003248.6(THBS4):c.1195-1246G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0215 in 152,320 control chromosomes in the GnomAD database, including 35 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 0.022 ( 35 hom., cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

THBS4
NM_003248.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.873

Publications

5 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=-0.88).

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0215 (3281/152320) while in subpopulation SAS AF = 0.0319 (154/4826). AF 95% confidence interval is 0.0278. There are 35 homozygotes in GnomAd4. There are 1574 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 35 AR gene

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	Effect	Exon Rank	Protein	UniProt
THBS4	NM_003248.6	MANE Select	c.1195-1246G>A	intron	N/A	NP_003239.2
THBS4	NM_001306212.2		c.922-1246G>A	intron	N/A	NP_001293141.1	E7ES19
THBS4	NM_001306213.2		c.922-1246G>A	intron	N/A	NP_001293142.1	E7ES19

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
THBS4	ENST00000350881.6	TSL:1 MANE Select	c.1195-1246G>A	intron	N/A	ENSP00000339730.2	P35443
THBS4-AS1	ENST00000514042.1	TSL:1	n.2327C>T	non_coding_transcript_exon	Exon 8 of 8
THBS4	ENST00000970348.1		c.1309-1246G>A	intron	N/A	ENSP00000640407.1

Frequencies

GnomAD3 genomes

AF:

0.0215

AC:

3273

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0246

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0187

Gnomad ASJ

AF:

0.0248

Gnomad EAS

AF:

0.0265

Gnomad SAS

AF:

0.0325

Gnomad FIN

AF:

0.00583

Gnomad MID

AF:

0.0475

Gnomad NFE

AF:

0.0215

Gnomad OTH

AF:

0.0224

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

Other (OTH)

AC:

AN:

GnomAD4 genome

AF:

0.0215

AC:

3281

AN:

152320

Hom.:

Cov.:

AF XY:

0.0211

AC XY:

1574

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.0247

AC:

1025

AN:

41566

American (AMR)

AF:

0.0186

AC:

285

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0248

AC:

AN:

3472

East Asian (EAS)

AF:

0.0264

AC:

137

AN:

5190

South Asian (SAS)

AF:

0.0319

AC:

154

AN:

4826

European-Finnish (FIN)

AF:

0.00583

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.0510

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0215

AC:

1461

AN:

68022

Other (OTH)

AF:

0.0260

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

173

347

520

694

867

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

160

200

<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:

0.0216

Hom.:

Bravo

AF:

0.0219

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

1.4

(source)

DANN

Benign

0.86

PhyloP100

-0.87

Mutation Taster

=100/0

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over