5-80058718-C-G

Variant names:

• chr5-80058718-C-G
• rs752816382
• NM_003248.6:c.660C>G

Variant summary

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

The NM_003248.6(THBS4):​c.660C>G​(p.Asn220Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,138 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: THBS4 NM_003248.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0120
• Publications: 0 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.660C>G	p.Asn220Lys	missense	Exon 5 of 22	NP_003239.2
	THBS4	NM_001306212.2		c.387C>G	p.Asn129Lys	missense	Exon 6 of 23	NP_001293141.1	E7ES19
	THBS4	NM_001306213.2		c.387C>G	p.Asn129Lys	missense	Exon 6 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.660C>G	p.Asn220Lys	missense	Exon 5 of 22	ENSP00000339730.2	P35443
	THBS4	ENST00000970348.1		c.774C>G	p.Asn258Lys	missense	Exon 5 of 22	ENSP00000640407.1
	THBS4	ENST00000854344.1		c.660C>G	p.Asn220Lys	missense	Exon 5 of 22	ENSP00000524403.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152138 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152138 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74296

African (AFR) AF: 0.0000241 AC: 1 AN: 41434

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

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	Uncertain	0.45
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.013	T
MetaRNN	Uncertain	0.59	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		-0.012
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.095
Sift	Benign	0.089	T
Sift4G	Benign	0.96	T
Polyphen		0.80	P
Vest4		0.73
MutPred		0.46		Gain of methylation at N220 (P = 0.0017)
MVP		0.42
MPC		0.97
ClinPred		0.63	D
GERP RS		1.7
Varity_R		0.14
gMVP		0.43
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs752816382; hg19: chr5-79354541;