Variant 5-80058287-A-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.622A>T(p.Ser208Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000108 in 1,567,904 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 0.00011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

THBS4
NM_003248.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.25

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:

Genome browser will be placed here

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=0.30292055).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
THBS4	NM_003248.6 linkuse as main transcript	c.622A>T	p.Ser208Cys	missense_variant	4/22	ENST00000350881.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
THBS4	ENST00000350881.6 linkuse as main transcript	c.622A>T	p.Ser208Cys	missense_variant	4/22	1	NM_003248.6	P1
THBS4-AS1	ENST00000503007.5 linkuse as main transcript	n.429-5386T>A		intron_variant, non_coding_transcript_variant		3
THBS4	ENST00000511733.1 linkuse as main transcript	c.349A>T	p.Ser117Cys	missense_variant	4/22	2

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152204

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000112

AC:

AN:

178282

Hom.:

AF XY:

0.0000845

AC XY:

AN XY:

94664

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000630

Gnomad NFE exome

AF:

0.000247

Gnomad OTH exome

AF:

0.000210

GnomAD4 exome

AF:

0.000108

AC:

153

AN:

1415700

Hom.:

Cov.:

AF XY:

0.000136

AC XY:

AN XY:

699780

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:

0.0000201

Gnomad4 NFE exome

AF:

0.000131

Gnomad4 OTH exome

AF:

0.000137

GnomAD4 genome

AF:

0.000112

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000250

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000193

Hom.:

Bravo

AF:

0.0000907

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000234

AC:

ExAC

AF:

0.000110

AC:

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

Sep 14, 2022

The c.622A>T (p.S208C) alteration is located in exon 4 (coding exon 4) of the THBS4 gene. This alteration results from a A to T substitution at nucleotide position 622, causing the serine (S) at amino acid position 208 to be replaced by a cysteine (C). 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

Uncertain

0.46

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.12

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.39

T;.

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.78

T;T

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.30

T;T

MetaSVM

Uncertain

0.24

MutationAssessor

Benign

1.7

L;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-2.1

N;N

REVEL

Uncertain

0.53

Sift

Benign

0.050

D;D

Sift4G

Uncertain

0.056

T;T

Polyphen

0.99

D;.

Vest4

0.35

MVP

0.94

MPC

0.89

ClinPred

0.25

GERP RS

5.7

Varity_R

0.18

gMVP

0.45

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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