Genetic Variant TMEM141:p.Pro18Ser (chr9-136791422-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_032928.4(TMEM141):c.52C>T(p.Pro18Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000223 in 1,557,450 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00023 ( 0 hom. )

Consequence

TMEM141
NM_032928.4 missense, splice_region

Scores

Splicing: ADA: 0.9755

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.01

Variant links:

Genes affected

TMEM141 (HGNC:28211): (transmembrane protein 141) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

TMEM141 links:

ENSG00000272896 (HGNC:):

ENSG00000272896 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 rank	MANE	Protein	UniProt
TMEM141	NM_032928.4 link	c.52C>T	p.Pro18Ser	missense_variant, splice_region_variant	Exon 1 of 5	ENST00000290079.9	NP_116317.1	Q96I45

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM141	ENST00000290079.9 link	c.52C>T	p.Pro18Ser	missense_variant, splice_region_variant	Exon 1 of 5	1	NM_032928.4	ENSP00000290079.8		Q96I45
ENSG00000272896	ENST00000456614.2 link	n.43C>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 1 of 6	4		ENSP00000476927.2		V9GYN2

Frequencies

GnomAD3 genomes

AF:

0.000131

AC:

AN:

152260

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.000235

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000703

AC:

AN:

156414

Hom.:

AF XY:

0.0000949

AC XY:

AN XY:

84298

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:

0.000187

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000233

AC:

328

AN:

1405190

Hom.:

Cov.:

AF XY:

0.000228

AC XY:

158

AN XY:

694112

show subpopulations

Gnomad4 AFR exome

AF:

0.0000313

Gnomad4 AMR exome

AF:

0.0000273

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000125

Gnomad4 FIN exome

AF:

0.0000208

Gnomad4 NFE exome

AF:

0.000293

Gnomad4 OTH exome

AF:

0.000103

GnomAD4 genome

AF:

0.000131

AC:

AN:

152260

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000235

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000116

Hom.:

Bravo

AF:

0.000125

ExAC

AF:

0.0000620

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 02, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.52C>T (p.P18S) alteration is located in exon 1 (coding exon 1) of the TMEM141 gene. This alteration results from a C to T substitution at nucleotide position 52, causing the proline (P) at amino acid position 18 to be replaced by a serine (S). 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

Uncertain

0.46

BayesDel_addAF

Benign

-0.046

BayesDel_noAF

Uncertain

-0.030

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Benign

0.64

LIST_S2

Benign

0.85

M_CAP

Pathogenic

0.83

MetaRNN

Uncertain

0.72

MetaSVM

Uncertain

-0.17

MutationAssessor

Uncertain

2.7

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-6.3

REVEL

Pathogenic

0.72

Sift

Uncertain

0.010

Sift4G

Uncertain

0.029

Polyphen

1.0

Vest4

0.48

MutPred

0.65

Gain of glycosylation at P18 (P = 0.0087);

MVP

0.040

MPC

0.59

ClinPred

0.87

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.48

gMVP

0.83

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.98

dbscSNV1_RF

Benign

0.46

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