5-80058776-C-G

Variant names:

• chr5-80058776-C-G
• rs137982040
• NM_003248.6:c.718C>G

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.718C>G​(p.Leu240Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L240F) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: THBS4 NM_003248.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.79
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14217696).

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.718C>G	p.Leu240Val	missense	Exon 5 of 22	NP_003239.2
	THBS4	NM_001306212.2		c.445C>G	p.Leu149Val	missense	Exon 6 of 23	NP_001293141.1	E7ES19
	THBS4	NM_001306213.2		c.445C>G	p.Leu149Val	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.718C>G	p.Leu240Val	missense	Exon 5 of 22	ENSP00000339730.2	P35443
	THBS4	ENST00000970348.1		c.832C>G	p.Leu278Val	missense	Exon 5 of 22	ENSP00000640407.1
	THBS4	ENST00000854344.1		c.718C>G	p.Leu240Val	missense	Exon 5 of 22	ENSP00000524403.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	20
DANN	Benign	0.76
DEOGEN2	Benign	0.049	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.019
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.60	N
PhyloP100		3.8
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.31	N
REVEL	Benign	0.039
Sift	Benign	0.69	T
Sift4G	Benign	0.36	T
Polyphen		0.011	B
Vest4		0.18
MutPred		0.36		Gain of loop (P = 0.0312)
MVP		0.51
MPC		0.90
ClinPred		0.93	D
GERP RS		5.0
Varity_R		0.071
gMVP		0.42
Mutation Taster		=80/20	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: rs137982040; hg19: chr5-79354599;