Variant 5-80059799-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_003248.6(THBS4):c.881C>T(p.Pro294Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000821 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

THBS4
NM_003248.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.09

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 made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3453436).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
THBS4	NM_003248.6 linkuse as main transcript	c.881C>T	p.Pro294Leu	missense_variant	7/22	ENST00000350881.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
THBS4	ENST00000350881.6 linkuse as main transcript	c.881C>T	p.Pro294Leu	missense_variant	7/22	1	NM_003248.6	P1
THBS4-AS1	ENST00000503007.5 linkuse as main transcript	n.429-6898G>A		intron_variant, non_coding_transcript_variant		3
THBS4	ENST00000511733.1 linkuse as main transcript	c.608C>T	p.Pro203Leu	missense_variant	7/22	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251490

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000821

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000108

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 10, 2021

The c.881C>T (p.P294L) alteration is located in exon 7 (coding exon 7) of the THBS4 gene. This alteration results from a C to T substitution at nucleotide position 881, causing the proline (P) at amino acid position 294 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.38

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.71

D;.

Eigen

Benign

0.16

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Uncertain

0.77

LIST_S2

Uncertain

0.92

D;D

M_CAP

Benign

0.015

MetaRNN

Benign

0.35

T;T

MetaSVM

Benign

-0.76

MutationAssessor

Uncertain

2.8

M;.

MutationTaster

Benign

0.98

N;N

PrimateAI

Benign

0.44

PROVEAN

Pathogenic

-5.7

D;D

REVEL

Benign

0.26

Sift

Benign

0.030

D;D

Sift4G

Uncertain

0.038

D;D

Polyphen

0.044

B;.

Vest4

0.30

MutPred

0.42

Loss of catalytic residue at P294 (P = 0.0069);.;

MVP

0.79

MPC

0.30

ClinPred

0.85

GERP RS

5.8

Varity_R

0.13

gMVP

0.81

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over