Genetic Variant TMEM270:p.Arg55Trp (chr7-73865083-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_182504.4(TMEM270):c.163C>T(p.Arg55Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0279 in 1,553,032 control chromosomes in the GnomAD database, including 727 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R55G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.023 ( 56 hom., cov: 33)

Exomes 𝑓: 0.028 ( 671 hom. )

Consequence

TMEM270
NM_182504.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.461

Publications

9 publications found

Variant links:

Genes affected

TMEM270 (HGNC:23018): (transmembrane protein 270) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

TMEM270 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=0.004664302).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0228 (3459/151662) while in subpopulation NFE AF = 0.0309 (2092/67808). AF 95% confidence interval is 0.0297. There are 56 homozygotes in GnomAd4. There are 1682 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 56 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM270	NM_182504.4 link	c.163C>T	p.Arg55Trp	missense_variant	Exon 2 of 3	ENST00000320531.3	NP_872310.2	Q6UE05-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TMEM270	ENST00000320531.3 link	c.163C>T	p.Arg55Trp	missense_variant	Exon 2 of 3	1	NM_182504.4	ENSP00000316775.2	Q6UE05-1
TMEM270	ENST00000426490.1 link	n.*103C>T		non_coding_transcript_exon_variant	Exon 3 of 4	5		ENSP00000403621.1	Q6UE05-2
TMEM270	ENST00000426490.1 link	n.*103C>T		3_prime_UTR_variant	Exon 3 of 4	5		ENSP00000403621.1	Q6UE05-2

Frequencies

GnomAD3 genomes

AF:

0.0228

AC:

3462

AN:

151538

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00943

Gnomad AMI

AF:

0.00220

Gnomad AMR

AF:

0.0165

Gnomad ASJ

AF:

0.0370

Gnomad EAS

AF:

0.000197

Gnomad SAS

AF:

0.0111

Gnomad FIN

AF:

0.0445

Gnomad MID

AF:

0.0478

Gnomad NFE

AF:

0.0309

Gnomad OTH

AF:

0.0274

GnomAD2 exomes

AF:

0.0249

AC:

5173

AN:

207600

AF XY:

0.0258

show subpopulations

Gnomad AFR exome

AF:

0.00891

Gnomad AMR exome

AF:

0.0168

Gnomad ASJ exome

AF:

0.0347

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0455

Gnomad NFE exome

AF:

0.0313

Gnomad OTH exome

AF:

0.0279

GnomAD4 exome

AF:

0.0284

AC:

39807

AN:

1401370

Hom.:

671

Cov.:

AF XY:

0.0284

AC XY:

19592

AN XY:

690746

show subpopulations

African (AFR)

AF:

0.00927

AC:

292

AN:

31508

American (AMR)

AF:

0.0176

AC:

630

AN:

35854

Ashkenazi Jewish (ASJ)

AF:

0.0358

AC:

801

AN:

22356

East Asian (EAS)

AF:

0.0000257

AC:

AN:

38836

South Asian (SAS)

AF:

0.0147

AC:

1128

AN:

76502

European-Finnish (FIN)

AF:

0.0479

AC:

2463

AN:

51462

Middle Eastern (MID)

AF:

0.0295

AC:

162

AN:

5494

European-Non Finnish (NFE)

AF:

0.0303

AC:

32774

AN:

1081712

Other (OTH)

AF:

0.0270

AC:

1556

AN:

57646

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

2355

4709

7064

9418

11773

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0228

AC:

3459

AN:

151662

Hom.:

Cov.:

AF XY:

0.0227

AC XY:

1682

AN XY:

74134

show subpopulations

African (AFR)

AF:

0.00943

AC:

390

AN:

41376

American (AMR)

AF:

0.0165

AC:

252

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.0370

AC:

128

AN:

3464

East Asian (EAS)

AF:

0.000197

AC:

AN:

5066

South Asian (SAS)

AF:

0.0111

AC:

AN:

4796

European-Finnish (FIN)

AF:

0.0445

AC:

471

AN:

10582

Middle Eastern (MID)

AF:

0.0479

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0309

AC:

2092

AN:

67808

Other (OTH)

AF:

0.0266

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

173

346

518

691

864

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0266

Hom.:

108

Bravo

AF:

0.0204

TwinsUK

AF:

0.0245

AC:

ALSPAC

AF:

0.0309

AC:

119

ESP6500AA

AF:

0.00863

AC:

ESP6500EA

AF:

0.0322

AC:

264

ExAC

AF:

0.0244

AC:

2942

Asia WGS

AF:

0.00549

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.69

CADD

Benign

6.8

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.023

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.027

LIST_S2

Benign

0.59

MetaRNN

Benign

0.0047

MetaSVM

Benign

-1.0

PhyloP100

-0.46

PrimateAI

Benign

0.20

PROVEAN

Uncertain

-2.5

REVEL

Benign

0.014

Sift

Benign

0.13

Sift4G

Benign

0.077

Polyphen

0.027

Vest4

0.031

MPC

0.021

ClinPred

0.012

GERP RS

1.4

Varity_R

0.063

gMVP

0.066

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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7-73865083-C-T

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