chr5-80059744-C-T

Variant names:

• chr5-80059744-C-T
• NM_003248.6:c.826C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003248.6(THBS4):​c.826C>T​(p.Pro276Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 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. P276T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: THBS4 NM_003248.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.400

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10939416).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THBS4	NM_003248.6	c.826C>T	p.Pro276Ser	missense_variant	Exon 7 of 22	ENST00000350881.6	NP_003239.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
THBS4	ENST00000350881.6	c.826C>T	p.Pro276Ser	missense_variant	Exon 7 of 22	1	NM_003248.6	ENSP00000339730.2
THBS4	ENST00000511733.1	c.553C>T	p.Pro185Ser	missense_variant	Exon 7 of 22	2		ENSP00000422298.1
THBS4-AS1	ENST00000503007.5	n.429-6843G>A		intron_variant	Intron 3 of 3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	9.3
DANN	Uncertain	0.99
DEOGEN2	Benign	0.075	T;.
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.77	T;T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.0	N;.
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.60	N;N
REVEL	Benign	0.22
Sift	Benign	0.18	T;T
Sift4G	Benign	0.34	T;T
Polyphen		0.0010	B;.
Vest4		0.27
MutPred		0.31		Loss of catalytic residue at P276 (P = 0.0012);.;
MVP		0.74
MPC		0.27
ClinPred		0.060	T
GERP RS		4.0
Varity_R		0.024
gMVP		0.48

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-79355567;