chr5-80065442-G-C

Variant names:

• chr5-80065442-G-C
• rs1866389
• NM_003248.6:c.1159G>C

Variant summary

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

The NM_003248.6(THBS4):​c.1159G>C​(p.Ala387Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.207 in 1,612,566 control chromosomes in the GnomAD database, including 36,494 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 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. A387T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.17 (2513 hom., cov: 32)
  • Exomes 𝑓: 0.21 (33981 hom.)
• Consequence: THBS4 NM_003248.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.01
• Publications: 78 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 (MetaRNN=0.0055117905).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.222 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.1159G>C	p.Ala387Pro	missense	Exon 9 of 22	NP_003239.2
	THBS4	NM_001306212.2		c.886G>C	p.Ala296Pro	missense	Exon 10 of 23	NP_001293141.1	E7ES19
	THBS4	NM_001306213.2		c.886G>C	p.Ala296Pro	missense	Exon 10 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.1159G>C	p.Ala387Pro	missense	Exon 9 of 22	ENSP00000339730.2	P35443
	THBS4	ENST00000970348.1		c.1273G>C	p.Ala425Pro	missense	Exon 9 of 22	ENSP00000640407.1
	THBS4	ENST00000854344.1		c.1159G>C	p.Ala387Pro	missense	Exon 9 of 22	ENSP00000524403.1

Frequencies

GnomAD3 genomes AF: 0.171 AC: 25955 AN: 152094 Hom.: 2508 Cov.: 32

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.234

Gnomad AMR AF: 0.150

Gnomad ASJ AF: 0.188

Gnomad EAS AF: 0.0496

Gnomad SAS AF: 0.177

Gnomad FIN AF: 0.165

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.225

Gnomad OTH AF: 0.187

GnomAD2 exomes AF: 0.173 AC: 43428 AN: 250482 AF XY: 0.180

Gnomad AFR exome AF: 0.101

Gnomad AMR exome AF: 0.106

Gnomad ASJ exome AF: 0.182

Gnomad EAS exome AF: 0.0399

Gnomad FIN exome AF: 0.165

Gnomad NFE exome AF: 0.221

Gnomad OTH exome AF: 0.203

GnomAD4 exome AF: 0.210 AC: 307178 AN: 1460354 Hom.: 33981 Cov.: 32 AF XY: 0.210 AC XY: 152425 AN XY: 726552

African (AFR) AF: 0.0960 AC: 3209 AN: 33420

American (AMR) AF: 0.113 AC: 5040 AN: 44480

Ashkenazi Jewish (ASJ) AF: 0.184 AC: 4807 AN: 26122

East Asian (EAS) AF: 0.0589 AC: 2335 AN: 39662

South Asian (SAS) AF: 0.185 AC: 15913 AN: 86066

European-Finnish (FIN) AF: 0.170 AC: 9093 AN: 53388

Middle Eastern (MID) AF: 0.228 AC: 1315 AN: 5768

European-Non Finnish (NFE) AF: 0.228 AC: 253579 AN: 1111116

Other (OTH) AF: 0.197 AC: 11887 AN: 60332

GnomAD4 genome AF: 0.171 AC: 25971 AN: 152212 Hom.: 2513 Cov.: 32 AF XY: 0.167 AC XY: 12423 AN XY: 74424

African (AFR) AF: 0.101 AC: 4212 AN: 41540

American (AMR) AF: 0.150 AC: 2289 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.188 AC: 651 AN: 3470

East Asian (EAS) AF: 0.0496 AC: 257 AN: 5186

South Asian (SAS) AF: 0.178 AC: 859 AN: 4820

European-Finnish (FIN) AF: 0.165 AC: 1746 AN: 10580

Middle Eastern (MID) AF: 0.252 AC: 74 AN: 294

European-Non Finnish (NFE) AF: 0.225 AC: 15282 AN: 68004

Other (OTH) AF: 0.184 AC: 389 AN: 2112

Alfa AF: 0.208 Hom.: 2677

Bravo AF: 0.166

TwinsUK AF: 0.232 AC: 859

ALSPAC AF: 0.237 AC: 915

ESP6500AA AF: 0.0994 AC: 438

ESP6500EA AF: 0.221 AC: 1903

ExAC AF: 0.178 AC: 21647

Asia WGS AF: 0.114 AC: 400 AN: 3478

EpiCase AF: 0.212

EpiControl AF: 0.218

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.42	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0055	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-1.2	N
PhyloP100		3.0
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.30
Sift	Uncertain	0.013	D
Sift4G	Benign	0.10	T
Polyphen		0.57	P
Vest4		0.39
MPC		0.88
ClinPred		0.015	T
GERP RS		5.2
Varity_R		0.46
gMVP		0.64
Mutation Taster		=94/6	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: rs1866389; hg19: chr5-79361265; COSMIC: COSV63469079; COSMIC: COSV63469079;