Genetic Variant TMEM222:p.Pro13Ser (chr1-27322234-C-T) – 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_032125.3(TMEM222):c.37C>T(p.Pro13Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000161 in 1,304,150 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P13L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

TMEM222
NM_032125.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.87

Publications

0 publications found

Variant links:

Genes affected

TMEM222 (HGNC:25363): (transmembrane protein 222) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

TMEM222 Gene-Disease associations (from GenCC):

neurodevelopmental disorder with motor and speech delay and behavioral abnormalities
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, LiferaOmics, Labcorp Genetics (formerly Invitae), G2P

TMEM222 links:

Genome browser will be placed here

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=0.23114008).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032125.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TMEM222	NM_032125.3	MANE Select	c.37C>T	p.Pro13Ser	missense	Exon 1 of 6	NP_115501.2	Q9H0R3-1
TMEM222	NR_037576.2		n.-11C>T		upstream_gene	N/A
TMEM222	NR_037577.2		n.-11C>T		upstream_gene	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TMEM222	ENST00000374076.9	TSL:1 MANE Select	c.37C>T	p.Pro13Ser	missense	Exon 1 of 6	ENSP00000363189.4	Q9H0R3-1
TMEM222	ENST00000611517.4	TSL:1	c.37C>T	p.Pro13Ser	missense	Exon 1 of 6	ENSP00000483276.1	Q9H0R3-1
TMEM222	ENST00000915856.1		c.37C>T	p.Pro13Ser	missense	Exon 1 of 6	ENSP00000585915.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

106854

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000161

AC:

AN:

1304150

Hom.:

Cov.:

AF XY:

0.0000156

AC XY:

AN XY:

639454

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27286

American (AMR)

AF:

0.0000472

AC:

AN:

21208

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19678

East Asian (EAS)

AF:

0.00

AC:

AN:

33070

South Asian (SAS)

AF:

0.00

AC:

AN:

68256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4916

European-Non Finnish (NFE)

AF:

0.0000184

AC:

AN:

1030164

Other (OTH)

AF:

0.0000189

AC:

AN:

52950

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000856

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Uncertain

0.048

BayesDel_noAF

Benign

-0.17

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.011

Eigen

Benign

0.17

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Benign

0.56

LIST_S2

Benign

0.75

M_CAP

Benign

0.0028

MetaRNN

Benign

0.23

MetaSVM

Benign

-0.87

MutationAssessor

Benign

0.69

PhyloP100

3.9

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-0.050

REVEL

Benign

0.10

Sift

Benign

0.090

Sift4G

Benign

0.19

Polyphen

0.95

Vest4

0.40

MutPred

0.16

Loss of catalytic residue at P13 (P = 0.0058)

MVP

0.40

MPC

0.38

ClinPred

0.49

GERP RS

4.5

PromoterAI

-0.0096

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.6

Varity_R

0.080

gMVP

0.75

Mutation Taster

=90/10

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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