NM_003248.6:c.423A>G

Variant names:

• chr5-80055915-A-G
• rs17882513
• NM_003248.6:c.423A>G

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_003248.6(THBS4):​c.423A>G​(p.Leu141Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00104 in 1,614,124 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0036 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00077 (1 hom.)
• Consequence: THBS4 NM_003248.6 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.126
• 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: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 5-80055915-A-G is Benign according to our data. Variant chr5-80055915-A-G is described in ClinVar as Benign. ClinVar VariationId is 783438.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.126 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

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.423A>G	p.Leu141Leu	synonymous	Exon 3 of 22	NP_003239.2
	THBS4	NM_001306212.2		c.150A>G	p.Leu50Leu	synonymous	Exon 4 of 23	NP_001293141.1	E7ES19
	THBS4	NM_001306213.2		c.150A>G	p.Leu50Leu	synonymous	Exon 4 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.423A>G	p.Leu141Leu	synonymous	Exon 3 of 22	ENSP00000339730.2	P35443
	THBS4	ENST00000970348.1		c.423A>G	p.Leu141Leu	synonymous	Exon 3 of 22	ENSP00000640407.1
	THBS4	ENST00000854344.1		c.423A>G	p.Leu141Leu	synonymous	Exon 3 of 22	ENSP00000524403.1

Frequencies

GnomAD3 genomes AF: 0.00355 AC: 541 AN: 152188 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.0104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00367

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.00718

GnomAD2 exomes AF: 0.00135 AC: 339 AN: 251484 AF XY: 0.00102

Gnomad AFR exome AF: 0.0102

Gnomad AMR exome AF: 0.00280

Gnomad ASJ exome AF: 0.000595

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000475

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.000774 AC: 1132 AN: 1461818 Hom.: 1 Cov.: 37 AF XY: 0.000666 AC XY: 484 AN XY: 727218

African (AFR) AF: 0.0104 AC: 348 AN: 33480

American (AMR) AF: 0.00295 AC: 132 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000842 AC: 22 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5768

European-Non Finnish (NFE) AF: 0.000468 AC: 520 AN: 1111950

Other (OTH) AF: 0.00159 AC: 96 AN: 60394

GnomAD4 genome AF: 0.00356 AC: 542 AN: 152306 Hom.: 3 Cov.: 33 AF XY: 0.00356 AC XY: 265 AN XY: 74480

African (AFR) AF: 0.0103 AC: 430 AN: 41564

American (AMR) AF: 0.00366 AC: 56 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000544 AC: 37 AN: 68016

Other (OTH) AF: 0.00710 AC: 15 AN: 2112

Alfa AF: 0.00179 Hom.: 0

Bravo AF: 0.00453

EpiCase AF: 0.000600

EpiControl AF: 0.000533

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.66
DANN	Benign	0.39
PhyloP100		-0.13
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs17882513; hg19: chr5-79351738;