chr5-80065475-T-G

Position:

• chr5-80065475-T-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000350881.6(THBS4):​c.1192T>G​(p.Leu398Val) variant causes a missense, splice region 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. 18/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: THBS4 ENST00000350881.6 missense, splice_region
• Scores: Splicing: ADA: 0.00005984
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.60

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:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.065499455).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
THBS4	NM_003248.6	c.1192T>G	p.Leu398Val	missense_variant, splice_region_variant	9/22	ENST00000350881.6	NP_003239.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
THBS4	ENST00000350881.6	c.1192T>G	p.Leu398Val	missense_variant, splice_region_variant	9/22	1	NM_003248.6	ENSP00000339730.2
THBS4	ENST00000511733.1	c.919T>G	p.Leu307Val	missense_variant, splice_region_variant	9/22	2		ENSP00000422298.1
THBS4-AS1	ENST00000661210.1	n.2761A>C		non_coding_transcript_exon_variant	3/3
THBS4-AS1	ENST00000503007.5	n.428+3039A>C		intron_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 24, 2023

The c.1192T>G (p.L398V) alteration is located in exon 9 (coding exon 9) of the THBS4 gene. This alteration results from a T to G substitution at nucleotide position 1192, causing the leucine (L) at amino acid position 398 to be replaced by a valine (V). 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	Benign	0.072
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	1.3
DANN	Benign	0.87
DEOGEN2	Benign	0.15	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.044	N
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.065	T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	-0.64	N;.
MutationTaster	Benign	0.96	N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.48	N;N
REVEL	Benign	0.17
Sift	Benign	1.0	T;T
Sift4G	Benign	0.71	T;T
Polyphen		0.0020	B;.
Vest4		0.12
MutPred		0.41		Loss of sheet (P = 0.0817);.;
MVP		0.53
MPC		0.26
ClinPred		0.061	T
GERP RS		-2.0
Varity_R		0.057
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000060
dbscSNV1_RF	Benign	0.018
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: chr5-79361298;