4-1717567-T-C

Variant names:

• chr4-1717567-T-C
• rs2236786
• NM_001127266.2:c.789A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_001127266.2(TMEM129):​c.789A>G​(p.Thr263Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.191 in 1,548,846 control chromosomes in the GnomAD database, including 29,881 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.16 (2440 hom., cov: 34)
  • Exomes 𝑓: 0.19 (27441 hom.)
• Consequence: TMEM129 NM_001127266.2 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.22
• Publications: 16 publications found

Genes affected

TMEM129 (HGNC:25137): (transmembrane protein 129, E3 ubiquitin ligase) Enables ubiquitin protein ligase activity. Involved in protein polyubiquitination; retrograde protein transport, ER to cytosol; and ubiquitin-dependent ERAD pathway. Located in endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

TACC3 (HGNC:11524): (transforming acidic coiled-coil containing protein 3) This gene encodes a member of the transforming acidic colied-coil protein family. The encoded protein is a motor spindle protein that may play a role in stabilization of the mitotic spindle. This protein may also play a role in growth a differentiation of certain cancer cells. [provided by RefSeq, Nov 2011]

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP7: Synonymous conserved (PhyloP=-4.22 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.243 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001127266.2. 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
	TMEM129	NM_001127266.2	MANE Select	c.789A>G	p.Thr263Thr	synonymous	Exon 3 of 4	NP_001120738.1
	TMEM129	NM_138385.4		c.681-139A>G		intron	N/A	NP_612394.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM129	ENST00000382936.8	TSL:1 MANE Select	c.789A>G	p.Thr263Thr	synonymous	Exon 3 of 4	ENSP00000372394.3
	TMEM129	ENST00000303277.6	TSL:1	c.681-139A>G		intron	N/A	ENSP00000305243.2
	TMEM129	ENST00000460722.1	TSL:1	n.*136A>G		non_coding_transcript_exon	Exon 2 of 3	ENSP00000417412.1

Frequencies

GnomAD3 genomes AF: 0.160 AC: 24318 AN: 152084 Hom.: 2440 Cov.: 34

Gnomad AFR AF: 0.0388

Gnomad AMI AF: 0.188

Gnomad AMR AF: 0.249

Gnomad ASJ AF: 0.230

Gnomad EAS AF: 0.142

Gnomad SAS AF: 0.216

Gnomad FIN AF: 0.229

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.195

Gnomad OTH AF: 0.182

GnomAD2 exomes AF: 0.210 AC: 31671 AN: 150554 AF XY: 0.209

Gnomad AFR exome AF: 0.0360

Gnomad AMR exome AF: 0.306

Gnomad ASJ exome AF: 0.227

Gnomad EAS exome AF: 0.133

Gnomad FIN exome AF: 0.222

Gnomad NFE exome AF: 0.198

Gnomad OTH exome AF: 0.209

GnomAD4 exome AF: 0.195 AC: 271707 AN: 1396644 Hom.: 27441 Cov.: 37 AF XY: 0.195 AC XY: 134453 AN XY: 688682

African (AFR) AF: 0.0326 AC: 1030 AN: 31564

American (AMR) AF: 0.297 AC: 10528 AN: 35440

Ashkenazi Jewish (ASJ) AF: 0.231 AC: 5779 AN: 25034

East Asian (EAS) AF: 0.153 AC: 5449 AN: 35720

South Asian (SAS) AF: 0.218 AC: 17211 AN: 78984

European-Finnish (FIN) AF: 0.218 AC: 10541 AN: 48438

Middle Eastern (MID) AF: 0.217 AC: 1235 AN: 5688

European-Non Finnish (NFE) AF: 0.194 AC: 208781 AN: 1077892

Other (OTH) AF: 0.193 AC: 11153 AN: 57884

GnomAD4 genome AF: 0.160 AC: 24309 AN: 152202 Hom.: 2440 Cov.: 34 AF XY: 0.165 AC XY: 12295 AN XY: 74404

African (AFR) AF: 0.0387 AC: 1609 AN: 41548

American (AMR) AF: 0.249 AC: 3811 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.230 AC: 798 AN: 3472

East Asian (EAS) AF: 0.142 AC: 736 AN: 5172

South Asian (SAS) AF: 0.215 AC: 1039 AN: 4826

European-Finnish (FIN) AF: 0.229 AC: 2432 AN: 10602

Middle Eastern (MID) AF: 0.207 AC: 61 AN: 294

European-Non Finnish (NFE) AF: 0.195 AC: 13273 AN: 67972

Other (OTH) AF: 0.179 AC: 379 AN: 2112

Alfa AF: 0.181 Hom.: 2925

Bravo AF: 0.156

Asia WGS AF: 0.162 AC: 560 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.7
DANN	Benign	0.57
PhyloP100		-4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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: rs2236786; hg19: chr4-1719294; COSMIC: COSV57559365; COSMIC: COSV57559365;