5-80059825-G-A

Variant summary

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

The NM_003248.6(THBS4):c.907G>A(p.Asp303Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000403 in 1,614,142 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000026 (0 hom.)
• Consequence: THBS4 NM_003248.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.67

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 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=0.03448972).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
THBS4	NM_003248.6	c.907G>A	p.Asp303Asn	missense_variant	7/22	ENST00000350881.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
THBS4	ENST00000350881.6	c.907G>A	p.Asp303Asn	missense_variant	7/22	1	NM_003248.6	P1
THBS4-AS1	ENST00000503007.5	n.429-6924C>T		intron_variant, non_coding_transcript_variant		3
THBS4	ENST00000511733.1	c.634G>A	p.Asp212Asn	missense_variant	7/22	2

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152140 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000517 AC: 13 AN: 251480 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135920

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000260 AC: 38 AN: 1461884 Hom.: 0 Cov.: 32 AF XY: 0.0000220 AC XY: 16 AN XY: 727246

Gnomad4 AFR exome AF: 0.000806

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152258 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74438

Gnomad4 AFR AF: 0.000578

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000263 Hom.: 0

Bravo AF: 0.000215

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000659 AC: 8

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

Oct 28, 2023

The c.907G>A (p.D303N) alteration is located in exon 7 (coding exon 7) of the THBS4 gene. This alteration results from a G to A substitution at nucleotide position 907, causing the aspartic acid (D) at amino acid position 303 to be replaced by an asparagine (N). 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	0.087
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.67
Cadd	Benign	17
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.49	T;.
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.69
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.77	T;T
M_CAP	Benign	0.0061	T
MetaRNN	Benign	0.034	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.30	N;.
MutationTaster	Benign	0.95	D;D
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.5	N;N
REVEL	Benign	0.12
Sift	Uncertain	0.026	D;D
Sift4G	Benign	0.17	T;T
Polyphen		0.0020	B;.
Vest4		0.16
MVP		0.39
MPC		0.25
ClinPred		0.065	T
GERP RS		-0.35
Varity_R		0.097
gMVP		0.57

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

LitVar

Other links and lift over

dbSNP: rs34249634; hg19: chr5-79355648; COSMIC: COSV63471114; COSMIC: COSV63471114;