5-80059700-T-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_003248.6(THBS4):c.785-3T>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00855 in 1,613,980 control chromosomes in the GnomAD database, including 99 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0059 (12 hom., cov: 32)
  • Exomes 𝑓: 0.0088 (87 hom.)
• Consequence: THBS4 NM_003248.6 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.9975
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.455

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 Likely_benign. Variant got -6 ACMG points.

• BP6: Variant 5-80059700-T-G is Benign according to our data. Variant chr5-80059700-T-G is described in ClinVar as [Benign]. Clinvar id is 3024840.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
THBS4	NM_003248.6	c.785-3T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000350881.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
THBS4	ENST00000350881.6	c.785-3T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_003248.6	P1
THBS4-AS1	ENST00000503007.5	n.429-6799A>C		intron_variant, non_coding_transcript_variant		3
THBS4	ENST00000511733.1	c.512-3T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.00593 AC: 903 AN: 152184 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.00171

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00499

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0109

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00631 AC: 1586 AN: 251230 Hom.: 11 AF XY: 0.00605 AC XY: 821 AN XY: 135788

Gnomad AFR exome AF: 0.00160

Gnomad AMR exome AF: 0.000810

Gnomad ASJ exome AF: 0.00209

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000425

Gnomad FIN exome AF: 0.00550

Gnomad NFE exome AF: 0.0119

Gnomad OTH exome AF: 0.00457

GnomAD4 exome AF: 0.00882 AC: 12897 AN: 1461678 Hom.: 87 Cov.: 32 AF XY: 0.00855 AC XY: 6216 AN XY: 727104

Gnomad4 AFR exome AF: 0.00114

Gnomad4 AMR exome AF: 0.000872

Gnomad4 ASJ exome AF: 0.00245

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000638

Gnomad4 FIN exome AF: 0.00625

Gnomad4 NFE exome AF: 0.0108

Gnomad4 OTH exome AF: 0.00601

GnomAD4 genome AF: 0.00593 AC: 903 AN: 152302 Hom.: 12 Cov.: 32 AF XY: 0.00552 AC XY: 411 AN XY: 74484

Gnomad4 AFR AF: 0.00171

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00432

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00499

Gnomad4 NFE AF: 0.0109

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00661 Hom.: 1

Bravo AF: 0.00541

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00856

EpiControl AF: 0.00747

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2023

THBS4: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
Cadd	Benign	18
Dann	Benign	0.64

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Benign	0.66
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.27		Position offset: 14

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

Publications

LitVar

Other links and lift over

dbSNP: rs115017662; hg19: chr5-79355523;