chr5-80059771-C-T

Variant names:

• chr5-80059771-C-T
• rs138755222
• NM_003248.6:c.853C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003248.6(THBS4):​c.853C>T​(p.Arg285Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000632 in 1,614,058 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R285G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000060 (0 hom.)
• Consequence: THBS4 NM_003248.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.686
• Publications: 4 publications found

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

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=0.1840092).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THBS4	NM_003248.6	MANE Select	c.853C>T	p.Arg285Cys	missense	Exon 7 of 22	NP_003239.2
	THBS4	NM_001306212.2		c.580C>T	p.Arg194Cys	missense	Exon 8 of 23	NP_001293141.1	E7ES19
	THBS4	NM_001306213.2		c.580C>T	p.Arg194Cys	missense	Exon 8 of 23	NP_001293142.1	E7ES19

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THBS4	ENST00000350881.6	TSL:1 MANE Select	c.853C>T	p.Arg285Cys	missense	Exon 7 of 22	ENSP00000339730.2	P35443
	THBS4	ENST00000970348.1		c.967C>T	p.Arg323Cys	missense	Exon 7 of 22	ENSP00000640407.1
	THBS4	ENST00000854344.1		c.853C>T	p.Arg285Cys	missense	Exon 7 of 22	ENSP00000524403.1

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.000118

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000557 AC: 14 AN: 251466 AF XY: 0.0000809

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000791

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000595 AC: 87 AN: 1461880 Hom.: 0 Cov.: 32 AF XY: 0.0000633 AC XY: 46 AN XY: 727244

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000671 AC: 3 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000665 AC: 74 AN: 1112008

Other (OTH) AF: 0.0000993 AC: 6 AN: 60396

GnomAD4 genome AF: 0.0000986 AC: 15 AN: 152178 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74334

African (AFR) AF: 0.000121 AC: 5 AN: 41446

American (AMR) AF: 0.0000654 AC: 1 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68026

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.0000772 Hom.: 0

Bravo AF: 0.0000604

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000576 AC: 7

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.83	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.69
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.12
Sift	Benign	0.13	T
Sift4G	Benign	0.097	T
Polyphen		0.39	B
Vest4		0.31
MVP		0.83
MPC		0.46
ClinPred		0.045	T
GERP RS		1.9
Varity_R		0.056
gMVP		0.70
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs138755222; hg19: chr5-79355594; COSMIC: COSV63469385; COSMIC: COSV63469385;