Variant 4-41949361-C-T details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_018126.3(TMEM33):c.590C>T(p.Ser197Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,457,770 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

TMEM33
NM_018126.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.32

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 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
TMEM33	NM_018126.3 linkuse as main transcript	c.590C>T	p.Ser197Leu	missense_variant	6/7	ENST00000504986.6	NP_060596.2	P57088A0A024R9W7
TMEM33	XM_005248116.5 linkuse as main transcript	c.590C>T	p.Ser197Leu	missense_variant	7/8		XP_005248173.1	P57088A0A024R9W7
TMEM33	XM_005248117.3 linkuse as main transcript	c.590C>T	p.Ser197Leu	missense_variant	7/8		XP_005248174.1	P57088A0A024R9W7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM33	ENST00000504986.6 linkuse as main transcript	c.590C>T	p.Ser197Leu	missense_variant	6/7	1	NM_018126.3	ENSP00000422473.1		P57088

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000404

AC:

AN:

247568

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134028

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000550

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000343

AC:

AN:

1457770

Hom.:

Cov.:

AF XY:

0.00000552

AC XY:

AN XY:

725248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

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

Mar 19, 2024

The c.590C>T (p.S197L) alteration is located in exon 6 (coding exon 6) of the TMEM33 gene. This alteration results from a C to T substitution at nucleotide position 590, causing the serine (S) at amino acid position 197 to be replaced by a leucine (L). 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

0.25

BayesDel_addAF

Uncertain

0.016

BayesDel_noAF

Uncertain

-0.040

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

T;.;T;T

Eigen

Uncertain

0.27

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

.;D;.;D

M_CAP

Benign

0.0095

MetaRNN

Uncertain

0.63

D;D;D;D

MetaSVM

Benign

-0.87

MutationAssessor

Benign

1.8

L;.;L;L

PrimateAI

Uncertain

0.75

PROVEAN

Uncertain

-2.6

D;D;D;D

REVEL

Uncertain

0.43

Sift

Uncertain

0.0030

D;T;D;D

Sift4G

Uncertain

0.012

D;D;D;D

Polyphen

0.70

P;.;P;P

Vest4

0.58

MutPred

0.58

Gain of glycosylation at S197 (P = 0.0201);Gain of glycosylation at S197 (P = 0.0201);Gain of glycosylation at S197 (P = 0.0201);Gain of glycosylation at S197 (P = 0.0201);

MVP

0.58

MPC

0.28

ClinPred

0.85

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.45

gMVP

0.71

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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