Genetic Variant TMEM200B:p.Met94Arg (chr1-29121548-A-C) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001003682.4(TMEM200B):c.281T>G(p.Met94Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00226 in 1,508,372 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0024 ( 5 hom. )

Consequence

TMEM200B
NM_001003682.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.898

Variant links:

Genes affected

TMEM200B (HGNC:33785): (transmembrane protein 200B) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

TMEM200B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008048385).

BS2

High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM200B	NM_001003682.4 link	c.281T>G	p.Met94Arg	missense_variant	Exon 2 of 2	ENST00000521452.2	NP_001003682.1	Q69YZ2
TMEM200B	NM_001171868.2 link	c.281T>G	p.Met94Arg	missense_variant	Exon 2 of 2		NP_001165339.1	Q69YZ2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM200B	ENST00000521452.2 link	c.281T>G	p.Met94Arg	missense_variant	Exon 2 of 2	1	NM_001003682.4	ENSP00000428459.1		Q69YZ2
TMEM200B	ENST00000420504.2 link	c.281T>G	p.Met94Arg	missense_variant	Exon 2 of 2	1		ENSP00000428544.1		Q69YZ2

Frequencies

GnomAD3 genomes

AF:

0.00142

AC:

216

AN:

151656

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000556

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000831

Gnomad FIN

AF:

0.00267

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00231

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00114

AC:

118

AN:

103874

Hom.:

AF XY:

0.00104

AC XY:

AN XY:

58510

show subpopulations

Gnomad AFR exome

AF:

0.000668

Gnomad AMR exome

AF:

0.000157

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000605

Gnomad FIN exome

AF:

0.00123

Gnomad NFE exome

AF:

0.00232

Gnomad OTH exome

AF:

0.000613

GnomAD4 exome

AF:

0.00236

AC:

3201

AN:

1356608

Hom.:

Cov.:

AF XY:

0.00227

AC XY:

1520

AN XY:

669808

show subpopulations

Gnomad4 AFR exome

AF:

0.000283

Gnomad4 AMR exome

AF:

0.000233

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000536

Gnomad4 FIN exome

AF:

0.00187

Gnomad4 NFE exome

AF:

0.00278

Gnomad4 OTH exome

AF:

0.00200

GnomAD4 genome

AF:

0.00142

AC:

215

AN:

151764

Hom.:

Cov.:

AF XY:

0.00132

AC XY:

AN XY:

74192

show subpopulations

Gnomad4 AFR

AF:

0.000555

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000832

Gnomad4 FIN

AF:

0.00267

Gnomad4 NFE

AF:

0.00230

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00115

Hom.:

Bravo

AF:

0.00120

ExAC

AF:

0.000352

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.281T>G (p.M94R) alteration is located in exon 2 (coding exon 1) of the TMEM200B gene. This alteration results from a T to G substitution at nucleotide position 281, causing the methionine (M) at amino acid position 94 to be replaced by an arginine (R). 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

0.079

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.51

CADD

Benign

9.5

DANN

Benign

0.52

DEOGEN2

Benign

0.0059

T;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.24

.;T

M_CAP

Benign

0.015

MetaRNN

Benign

0.0080

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

N;N

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

0.30

N;N

REVEL

Benign

0.035

Sift

Benign

0.61

T;T

Sift4G

Uncertain

0.024

D;D

Polyphen

0.0050

B;B

Vest4

0.089

MVP

0.030

MPC

1.2

ClinPred

0.0014

GERP RS

0.34

Varity_R

0.14

gMVP

0.37

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