Genetic Variant TMEM225:p.Cys154Ser (chr11-123884077-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001013743.3(TMEM225):c.461G>C(p.Cys154Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000249 in 1,607,574 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. C154Y) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

TMEM225
NM_001013743.3 missense, splice_region

Scores

Splicing: ADA: 0.00004511

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.691

Publications

1 publications found

Variant links:

Genes affected

TMEM225 (HGNC:32390): (transmembrane protein 225) Predicted to be involved in negative regulation of phosphatase activity. Predicted to be located in acrosomal membrane. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

TMEM225 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08400458).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001013743.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM225	NM_001013743.3	MANE Select	c.461G>C	p.Cys154Ser	missense splice_region	Exon 3 of 4	NP_001013765.2	Q6GV28
	TMEM225	NM_001363605.2		c.311G>C	p.Cys104Ser	missense splice_region	Exon 3 of 4	NP_001350534.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM225	ENST00000375026.7	TSL:1 MANE Select	c.461G>C	p.Cys154Ser	missense splice_region	Exon 3 of 4	ENSP00000364166.2	Q6GV28
	TMEM225	ENST00000528595.1	TSL:3	c.311G>C	p.Cys104Ser	missense splice_region	Exon 3 of 4	ENSP00000431282.1	E9PLT9

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151964

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1455610

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

724094

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33034

American (AMR)

AF:

0.00

AC:

AN:

43716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25712

East Asian (EAS)

AF:

0.00

AC:

AN:

39588

South Asian (SAS)

AF:

0.0000352

AC:

AN:

85212

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53230

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5710

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1109308

Other (OTH)

AF:

0.00

AC:

AN:

60100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151964

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74218

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41360

American (AMR)

AF:

0.00

AC:

AN:

15240

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000207

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10588

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67982

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Benign

-0.086

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Benign

0.75

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.56

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.33

M_CAP

Benign

0.0075

MetaRNN

Benign

0.084

MetaSVM

Benign

-1.0

PhyloP100

0.69

PrimateAI

Benign

0.30

PROVEAN

Uncertain

-4.0

REVEL

Benign

0.17

Sift

Benign

0.79

Sift4G

Benign

1.0

Vest4

0.073

MutPred

0.46

Gain of sheet (P = 0.0344)

MVP

0.34

MPC

0.54

ClinPred

0.24

GERP RS

2.8

gMVP

0.086

Mutation Taster

=92/8

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000045

dbscSNV1_RF

Benign

0.0060

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over