NM_003248.6:c.622A>T

Variant names:

• chr5-80058287-A-T
• rs151176433
• NM_003248.6:c.622A>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_003248.6(THBS4):​c.622A>T​(p.Ser208Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000108 in 1,567,904 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: THBS4 NM_003248.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.25
• Publications: 3 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: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.30292055).

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.622A>T	p.Ser208Cys	missense	Exon 4 of 22	NP_003239.2
	THBS4	NM_001306212.2		c.349A>T	p.Ser117Cys	missense	Exon 5 of 23	NP_001293141.1	E7ES19
	THBS4	NM_001306213.2		c.349A>T	p.Ser117Cys	missense	Exon 5 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.622A>T	p.Ser208Cys	missense	Exon 4 of 22	ENSP00000339730.2	P35443
	THBS4	ENST00000970348.1		c.622A>T	p.Ser208Cys	missense	Exon 4 of 22	ENSP00000640407.1
	THBS4	ENST00000854344.1		c.622A>T	p.Ser208Cys	missense	Exon 4 of 22	ENSP00000524403.1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152204 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000112 AC: 20 AN: 178282 AF XY: 0.0000845

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000630

Gnomad NFE exome AF: 0.000247

Gnomad OTH exome AF: 0.000210

GnomAD4 exome AF: 0.000108 AC: 153 AN: 1415700 Hom.: 0 Cov.: 31 AF XY: 0.000136 AC XY: 95 AN XY: 699780

African (AFR) AF: 0.00 AC: 0 AN: 32480

American (AMR) AF: 0.00 AC: 0 AN: 38732

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25304

East Asian (EAS) AF: 0.00 AC: 0 AN: 37456

South Asian (SAS) AF: 0.00 AC: 0 AN: 80432

European-Finnish (FIN) AF: 0.0000201 AC: 1 AN: 49650

Middle Eastern (MID) AF: 0.000350 AC: 2 AN: 5714

European-Non Finnish (NFE) AF: 0.000131 AC: 142 AN: 1087352

Other (OTH) AF: 0.000137 AC: 8 AN: 58580

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152204 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74370

African (AFR) AF: 0.00 AC: 0 AN: 41446

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000193 Hom.: 0

Bravo AF: 0.0000907

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000234 AC: 2

ExAC AF: 0.000110 AC: 13

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.78	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.30	T
MetaSVM	Uncertain	0.24	D
MutationAssessor	Benign	1.7	L
PhyloP100		5.2
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.53
Sift	Benign	0.050	D
Sift4G	Uncertain	0.056	T
Polyphen		0.99	D
Vest4		0.35
MVP		0.94
MPC		0.89
ClinPred		0.25	T
GERP RS		5.7
Varity_R		0.18
gMVP		0.45
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs151176433; hg19: chr5-79354110;