chr18-9399458-C-T

Variant names:

• chr18-9399458-C-T
• rs138769456
• NM_020648.6:c.603C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Moderate BP6_Moderate BP7 BS2

The NM_020648.6(TWSG1):​c.603C>T​(p.Cys201Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000387 in 1,613,938 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00091 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00033 (0 hom.)
• Consequence: TWSG1 NM_020648.6 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.57
• 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 18-9399458-C-T is Benign according to our data. Variant chr18-9399458-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2648566.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-1.57 with no splicing effect.
• BS2: High AC in GnomAd4 at 138 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.603C>T	p.Cys201Cys	synonymous	Exon 5 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.603C>T	p.Cys201Cys	synonymous	Exon 5 of 5	ENSP00000262120.5	Q9GZX9-1
	TWSG1	ENST00000951397.1		c.726C>T	p.Cys242Cys	synonymous	Exon 6 of 6	ENSP00000621456.1
	TWSG1	ENST00000934387.1		c.603C>T	p.Cys201Cys	synonymous	Exon 5 of 5	ENSP00000604446.1

Frequencies

GnomAD3 genomes AF: 0.000868 AC: 132 AN: 152126 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00162

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000541 AC: 136 AN: 251218 AF XY: 0.000486

Gnomad AFR exome AF: 0.00166

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000475

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000332 AC: 486 AN: 1461694 Hom.: 0 Cov.: 31 AF XY: 0.000336 AC XY: 244 AN XY: 727166

African (AFR) AF: 0.00173 AC: 58 AN: 33472

American (AMR) AF: 0.00101 AC: 45 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.000880 AC: 23 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00 AC: 0 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00347 AC: 20 AN: 5768

European-Non Finnish (NFE) AF: 0.000255 AC: 284 AN: 1111920

Other (OTH) AF: 0.000928 AC: 56 AN: 60376

GnomAD4 genome AF: 0.000906 AC: 138 AN: 152244 Hom.: 0 Cov.: 32 AF XY: 0.000752 AC XY: 56 AN XY: 74440

African (AFR) AF: 0.00176 AC: 73 AN: 41538

American (AMR) AF: 0.00157 AC: 24 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

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

European-Non Finnish (NFE) AF: 0.000500 AC: 34 AN: 68018

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000701 Hom.: 0

Bravo AF: 0.000839

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000356

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	-0.32
CADD	Benign	2.4
DANN	Benign	0.54
PhyloP100		-1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	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: rs138769456; hg19: chr18-9399456; COSMIC: COSV50815882; COSMIC: COSV50815882;