Variant 4-41938656-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The ENST00000504986.6(TMEM33):c.100A>G(p.Thr34Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,790 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TMEM33
ENST00000504986.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.10

Variant links:

Genes affected

TMEM33 (HGNC:25541): (transmembrane protein 33) Involved in positive regulation of endoplasmic reticulum unfolded protein response; regulation of endoplasmic reticulum tubular network organization; and response to endoplasmic reticulum stress. Located in endoplasmic reticulum membrane; melanosome; and nuclear envelope. Is integral component of endoplasmic reticulum membrane. [provided by Alliance of Genome Resources, Apr 2022]

TMEM33 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.867

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TMEM33	NM_018126.3 linkuse as main transcript	c.100A>G	p.Thr34Ala	missense_variant	2/7	ENST00000504986.6	NP_060596.2
TMEM33	XM_005248116.5 linkuse as main transcript	c.100A>G	p.Thr34Ala	missense_variant	3/8		XP_005248173.1
TMEM33	XM_005248117.3 linkuse as main transcript	c.100A>G	p.Thr34Ala	missense_variant	3/8		XP_005248174.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM33	ENST00000504986.6 linkuse as main transcript	c.100A>G	p.Thr34Ala	missense_variant	2/7	1	NM_018126.3	ENSP00000422473	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461790

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727202

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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

Mar 16, 2022

The c.100A>G (p.T34A) alteration is located in exon 2 (coding exon 2) of the TMEM33 gene. This alteration results from a A to G substitution at nucleotide position 100, causing the threonine (T) at amino acid position 34 to be replaced by an alanine (A). 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

Pathogenic

0.83

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

T;.;T;T

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.89

.;D;.;D

M_CAP

Benign

0.031

MetaRNN

Pathogenic

0.87

D;D;D;D

MetaSVM

Uncertain

-0.18

MutationAssessor

Uncertain

2.3

M;.;M;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.82

PROVEAN

Uncertain

-3.4

D;D;D;D

REVEL

Pathogenic

0.68

Sift

Benign

0.050

D;T;D;D

Sift4G

Uncertain

0.040

D;D;D;D

Polyphen

1.0

D;.;D;D

Vest4

0.90

MutPred

0.73

Gain of glycosylation at T34 (P = 0.1527);Gain of glycosylation at T34 (P = 0.1527);Gain of glycosylation at T34 (P = 0.1527);Gain of glycosylation at T34 (P = 0.1527);

MVP

0.47

MPC

0.73

ClinPred

0.96

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.39

gMVP

0.78

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over