Variant chr4-1718227-T-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000382936.8(TMEM129):c.605A>T(p.Asp202Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000275 in 1,602,130 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

TMEM129
ENST00000382936.8 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.34

Variant links:

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]

TMEM129 links:

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]

TACC3 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM129	NM_001127266.2 linkuse as main transcript	c.605A>T	p.Asp202Val	missense_variant	2/4	ENST00000382936.8	NP_001120738.1	A0AVI4-1
TMEM129	NM_138385.4 linkuse as main transcript	c.605A>T	p.Asp202Val	missense_variant	2/3		NP_612394.1	A0AVI4-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TMEM129	ENST00000382936.8 linkuse as main transcript	c.605A>T	p.Asp202Val	missense_variant	2/4	1	NM_001127266.2	ENSP00000372394.3	A0AVI4-1
TMEM129	ENST00000303277.6 linkuse as main transcript	c.605A>T	p.Asp202Val	missense_variant	2/3	1		ENSP00000305243.2	A0AVI4-2
TMEM129	ENST00000460722.1 linkuse as main transcript	n.8A>T		non_coding_transcript_exon_variant	1/3	1		ENSP00000417412.1	H7C4I8
TACC3	ENST00000458173.4 linkuse as main transcript	c.-2+5062T>A		intron_variant		5		ENSP00000415914.4	E7EMT0

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152068

Hom.:

Cov.:

show subpopulations

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000521

AC:

AN:

230526

Hom.:

AF XY:

0.0000240

AC XY:

AN XY:

124872

show subpopulations

Gnomad AFR exome

AF:

0.0000703

Gnomad AMR exome

AF:

0.0000918

Gnomad ASJ exome

AF:

0.000209

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000583

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000283

AC:

AN:

1449944

Hom.:

Cov.:

AF XY:

0.0000250

AC XY:

AN XY:

720256

show subpopulations

Gnomad4 AFR exome

AF:

0.0000301

Gnomad4 AMR exome

AF:

0.0000926

Gnomad4 ASJ exome

AF:

0.000193

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000253

Gnomad4 OTH exome

AF:

0.0000333

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74402

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000959

Hom.:

Bravo

AF:

0.0000264

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 07, 2022

The c.605A>T (p.D202V) alteration is located in exon 2 (coding exon 2) of the TMEM129 gene. This alteration results from a A to T substitution at nucleotide position 605, causing the aspartic acid (D) at amino acid position 202 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Uncertain

0.034

BayesDel_noAF

Uncertain

0.010

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.13

.;T;T

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

D;.;D

M_CAP

Uncertain

0.18

MetaRNN

Uncertain

0.68

D;D;D

MetaSVM

Benign

-0.53

MutationAssessor

Uncertain

2.3

M;M;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-3.0

D;D;D

REVEL

Uncertain

0.41

Sift

Uncertain

0.0030

D;T;T

Sift4G

Uncertain

0.0060

D;T;T

Polyphen

0.96

D;P;P

Vest4

0.83

MVP

0.44

MPC

0.64

ClinPred

0.40

GERP RS

4.6

Varity_R

0.54

gMVP

0.63

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over