4-1718248-C-T

Position:

chr4-1718248-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_001127266.2(TMEM129):c.584G>A(p.Arg195Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000249 in 1,607,934 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

TMEM129
NM_001127266.2 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.31

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 Likely_benign. Variant got -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.055425197).

BP6

Variant 4-1718248-C-T is Benign according to our data. Variant chr4-1718248-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3178546.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM129	NM_001127266.2 linkuse as main transcript	c.584G>A	p.Arg195Gln	missense_variant	2/4	ENST00000382936.8	NP_001120738.1
TMEM129	NM_138385.4 linkuse as main transcript	c.584G>A	p.Arg195Gln	missense_variant	2/3		NP_612394.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM129	ENST00000382936.8 linkuse as main transcript	c.584G>A	p.Arg195Gln	missense_variant	2/4	1	NM_001127266.2	ENSP00000372394	P1	A0AVI4-1
TMEM129	ENST00000303277.6 linkuse as main transcript	c.584G>A	p.Arg195Gln	missense_variant	2/3	1		ENSP00000305243		A0AVI4-2
TACC3	ENST00000458173.4 linkuse as main transcript	c.-2+5083C>T		intron_variant		5		ENSP00000415914
TMEM129	ENST00000460722.1 linkuse as main transcript			upstream_gene_variant		1		ENSP00000417412

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152142

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000416

AC:

AN:

240346

Hom.:

AF XY:

0.00000767

AC XY:

AN XY:

130300

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000924

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1455792

Hom.:

Cov.:

AF XY:

0.00000415

AC XY:

AN XY:

723670

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152142

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74308

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 13, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.56

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.0058

.;T;T

Eigen

Benign

-0.97

Eigen_PC

Benign

-0.89

FATHMM_MKL

Uncertain

0.77

LIST_S2

Uncertain

0.88

D;.;D

M_CAP

Benign

0.016

MetaRNN

Benign

0.055

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.4

L;L;L

MutationTaster

Benign

0.99

N;N;N

PrimateAI

Benign

0.21

PROVEAN

Benign

1.1

N;N;N

REVEL

Benign

0.025

Sift

Benign

0.75

T;T;T

Sift4G

Benign

0.50

T;T;T

Polyphen

0.0090

B;B;B

Vest4

0.12

MutPred

0.35

Gain of loop (P = 0.0851);Gain of loop (P = 0.0851);Gain of loop (P = 0.0851);

MVP

0.21

MPC

0.26

ClinPred

0.044

GERP RS

1.7

Varity_R

0.026

gMVP

0.20

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