rs404375

Variant names:

• chr5-80052936-G-A
• rs404375
• NM_003248.6:c.293-2849G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003248.6(THBS4):​c.293-2849G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.549 in 152,024 control chromosomes in the GnomAD database, including 23,380 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.55 (23380 hom., cov: 32)
  • Exomes 𝑓: 0.50 (0 hom.)
• Consequence: THBS4 NM_003248.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.584
• Publications: 6 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.648 is higher than 0.05.

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.293-2849G>A		intron	N/A	NP_003239.2
	THBS4	NM_001306212.2		c.20-2849G>A		intron	N/A	NP_001293141.1
	THBS4	NM_001306213.2		c.20-2849G>A		intron	N/A	NP_001293142.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THBS4	ENST00000350881.6	TSL:1 MANE Select	c.293-2849G>A		intron	N/A	ENSP00000339730.2
	THBS4	ENST00000970348.1		c.293-2849G>A		intron	N/A	ENSP00000640407.1
	THBS4	ENST00000854344.1		c.293-2849G>A		intron	N/A	ENSP00000524403.1

Frequencies

GnomAD3 genomes AF: 0.549 AC: 83419 AN: 151908 Hom.: 23347 Cov.: 32

Gnomad AFR AF: 0.654

Gnomad AMI AF: 0.720

Gnomad AMR AF: 0.528

Gnomad ASJ AF: 0.560

Gnomad EAS AF: 0.489

Gnomad SAS AF: 0.544

Gnomad FIN AF: 0.494

Gnomad MID AF: 0.620

Gnomad NFE AF: 0.500

Gnomad OTH AF: 0.545

GnomAD4 exome AF: 0.500 AC: 1 AN: 2 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.500 AC: 1 AN: 2

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.549 AC: 83512 AN: 152022 Hom.: 23380 Cov.: 32 AF XY: 0.547 AC XY: 40632 AN XY: 74298

African (AFR) AF: 0.654 AC: 27141 AN: 41494

American (AMR) AF: 0.529 AC: 8064 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.560 AC: 1943 AN: 3470

East Asian (EAS) AF: 0.489 AC: 2528 AN: 5166

South Asian (SAS) AF: 0.544 AC: 2622 AN: 4820

European-Finnish (FIN) AF: 0.494 AC: 5207 AN: 10542

Middle Eastern (MID) AF: 0.627 AC: 183 AN: 292

European-Non Finnish (NFE) AF: 0.500 AC: 34014 AN: 67960

Other (OTH) AF: 0.546 AC: 1153 AN: 2110

Alfa AF: 0.520 Hom.: 65216

Bravo AF: 0.560

Asia WGS AF: 0.562 AC: 1957 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	3.1
DANN	Benign	0.64
PhyloP100		0.58
Mutation Taster		=100/0	polymorphism (auto)

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: rs404375; hg19: chr5-79348759; COSMIC: COSV63468411;