Genetic Variant TMEM254:p.Cys93Phe (chr10-80081936-G-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000613758.4(TMEM254):c.278G>T(p.Cys93Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.416 in 1,612,638 control chromosomes in the GnomAD database, including 143,571 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/14 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.38 ( 11637 hom., cov: 32)

Exomes 𝑓: 0.42 ( 131934 hom. )

Consequence

TMEM254
ENST00000613758.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.258

Publications

28 publications found

Variant links:

Genes affected

TMEM254 (HGNC:25804): (transmembrane protein 254) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

TMEM254 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=6.516193E-6).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.687 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM254	NM_025125.4 link	c.183G>T	p.Leu61Leu	synonymous_variant	Exon 2 of 4	ENST00000372281.8	NP_079401.2	Q8TBM7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM254	ENST00000372281.8 link	c.183G>T	p.Leu61Leu	synonymous_variant	Exon 2 of 4	1	NM_025125.4	ENSP00000361355.3		Q8TBM7-1

Frequencies

GnomAD3 genomes

AF:

0.378

AC:

57418

AN:

151858

Hom.:

11644

Cov.:

show subpopulations

Gnomad AFR

AF:

0.255

Gnomad AMI

AF:

0.580

Gnomad AMR

AF:

0.331

Gnomad ASJ

AF:

0.405

Gnomad EAS

AF:

0.707

Gnomad SAS

AF:

0.449

Gnomad FIN

AF:

0.411

Gnomad MID

AF:

0.459

Gnomad NFE

AF:

0.424

Gnomad OTH

AF:

0.386

GnomAD2 exomes

AF:

0.413

AC:

103768

AN:

251284

AF XY:

0.420

show subpopulations

Gnomad AFR exome

AF:

0.257

Gnomad AMR exome

AF:

0.278

Gnomad ASJ exome

AF:

0.400

Gnomad EAS exome

AF:

0.709

Gnomad FIN exome

AF:

0.405

Gnomad NFE exome

AF:

0.424

Gnomad OTH exome

AF:

0.407

GnomAD4 exome

AF:

0.420

AC:

614116

AN:

1460660

Hom.:

131934

Cov.:

AF XY:

0.422

AC XY:

306890

AN XY:

726716

show subpopulations

African (AFR)

AF:

0.248

AC:

8289

AN:

33468

American (AMR)

AF:

0.281

AC:

12582

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.403

AC:

10521

AN:

26132

East Asian (EAS)

AF:

0.694

AC:

27540

AN:

39692

South Asian (SAS)

AF:

0.443

AC:

38187

AN:

86214

European-Finnish (FIN)

AF:

0.408

AC:

21760

AN:

53298

Middle Eastern (MID)

AF:

0.396

AC:

2283

AN:

5762

European-Non Finnish (NFE)

AF:

0.421

AC:

467419

AN:

1111016

Other (OTH)

AF:

0.423

AC:

25535

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

18175

36349

54524

72698

90873

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14282

28564

42846

57128

71410

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.378

AC:

57428

AN:

151978

Hom.:

11637

Cov.:

AF XY:

0.380

AC XY:

28199

AN XY:

74262

show subpopulations

African (AFR)

AF:

0.255

AC:

10561

AN:

41474

American (AMR)

AF:

0.331

AC:

5058

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.405

AC:

1406

AN:

3468

East Asian (EAS)

AF:

0.707

AC:

3625

AN:

5130

South Asian (SAS)

AF:

0.450

AC:

2163

AN:

4812

European-Finnish (FIN)

AF:

0.411

AC:

4331

AN:

10542

Middle Eastern (MID)

AF:

0.449

AC:

131

AN:

292

European-Non Finnish (NFE)

AF:

0.424

AC:

28806

AN:

67946

Other (OTH)

AF:

0.387

AC:

818

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

1722

3444

5165

6887

8609

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

560

1120

1680

2240

2800

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.397

Hom.:

31097

Bravo

AF:

0.364

TwinsUK

AF:

0.429

AC:

1591

ALSPAC

AF:

0.426

AC:

1640

ESP6500AA

AF:

0.268

AC:

1179

ESP6500EA

AF:

0.428

AC:

3678

ExAC

AF:

0.415

AC:

50399

Asia WGS

AF:

0.530

AC:

1841

AN:

3478

EpiCase

AF:

0.421

EpiControl

AF:

0.422

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.83

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.72

(source)

DANN

Benign

0.73

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.52

FATHMM_MKL

Benign

0.026

LIST_S2

Benign

0.30

MetaRNN

Benign

0.0000065

MetaSVM

Benign

-0.96

PhyloP100

-0.26

Vest4

0.54

ClinPred

0.00026

GERP RS

1.3

PromoterAI

-0.0068

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over