18-9359992-G-A

Variant names:

• chr18-9359992-G-A
• rs142770364
• NM_020648.6:c.144G>A

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_020648.6(TWSG1):​c.144G>A​(p.Pro48Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00575 in 1,613,184 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0049 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0058 (50 hom.)
• Consequence: TWSG1 NM_020648.6 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.971
• Publications: 3 publications found

Genes affected

TWSG1 (HGNC:12429): (twisted gastrulation BMP signaling modulator 1) Enables transforming growth factor beta binding activity. Involved in several processes, including negative regulation of CD4-positive, alpha-beta T cell proliferation; positive regulation of pathway-restricted SMAD protein phosphorylation; and transforming growth factor beta receptor signaling pathway. Predicted to be located in extracellular region. Predicted to be active in extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 18-9359992-G-A is Benign according to our data. Variant chr18-9359992-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2648565.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.971 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00584 (8536/1460940) while in subpopulation MID AF = 0.0352 (203/5762). AF 95% confidence interval is 0.0313. There are 50 homozygotes in GnomAdExome4. There are 4353 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High AC in GnomAd4 at 741 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020648.6. 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
	TWSG1	NM_020648.6	MANE Select	c.144G>A	p.Pro48Pro	synonymous	Exon 3 of 5	NP_065699.1	Q9GZX9-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TWSG1	ENST00000262120.10	TSL:1 MANE Select	c.144G>A	p.Pro48Pro	synonymous	Exon 3 of 5	ENSP00000262120.5	Q9GZX9-1
	TWSG1	ENST00000951397.1		c.144G>A	p.Pro48Pro	synonymous	Exon 3 of 6	ENSP00000621456.1
	TWSG1	ENST00000934387.1		c.144G>A	p.Pro48Pro	synonymous	Exon 3 of 5	ENSP00000604446.1

Frequencies

GnomAD3 genomes AF: 0.00488 AC: 743 AN: 152126 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00135

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00714

Gnomad ASJ AF: 0.0205

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.00673

Gnomad OTH AF: 0.00766

GnomAD2 exomes AF: 0.00547 AC: 1374 AN: 251324 AF XY: 0.00580

Gnomad AFR exome AF: 0.00166

Gnomad AMR exome AF: 0.00466

Gnomad ASJ exome AF: 0.0221

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000508

Gnomad NFE exome AF: 0.00689

Gnomad OTH exome AF: 0.00734

GnomAD4 exome AF: 0.00584 AC: 8536 AN: 1460940 Hom.: 50 Cov.: 30 AF XY: 0.00599 AC XY: 4353 AN XY: 726776

African (AFR) AF: 0.00182 AC: 61 AN: 33464

American (AMR) AF: 0.00494 AC: 221 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.0221 AC: 577 AN: 26112

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39658

South Asian (SAS) AF: 0.00436 AC: 376 AN: 86172

European-Finnish (FIN) AF: 0.000525 AC: 28 AN: 53332

Middle Eastern (MID) AF: 0.0352 AC: 203 AN: 5762

European-Non Finnish (NFE) AF: 0.00595 AC: 6614 AN: 1111402

Other (OTH) AF: 0.00754 AC: 455 AN: 60328

GnomAD4 genome AF: 0.00487 AC: 741 AN: 152244 Hom.: 5 Cov.: 32 AF XY: 0.00439 AC XY: 327 AN XY: 74432

African (AFR) AF: 0.00132 AC: 55 AN: 41554

American (AMR) AF: 0.00713 AC: 109 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0205 AC: 71 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00270 AC: 13 AN: 4822

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10606

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.00673 AC: 458 AN: 68012

Other (OTH) AF: 0.00758 AC: 16 AN: 2110

Alfa AF: 0.00734 Hom.: 1

Bravo AF: 0.00519

Asia WGS AF: 0.00260 AC: 10 AN: 3478

EpiCase AF: 0.00902

EpiControl AF: 0.0103

ClinVar

ClinVar submissions

Significance: Likely 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	-0.80
CADD	Benign	3.3
DANN	Benign	0.52
PhyloP100		-0.97
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	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: rs142770364; hg19: chr18-9359990; COSMIC: COSV50815291;