Genetic Variant TMEM222:p.Ala29Glu (chr1-27322283-C-A) – 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.86C>A(p.Ala29Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000716 in 1,397,132 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. 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. A29T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

TMEM222
NM_032125.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.914

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=0.08704075).

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.86C>A	p.Ala29Glu	missense	Exon 1 of 6	NP_115501.2	Q9H0R3-1
TMEM222	NR_037576.2		n.39C>A		non_coding_transcript_exon	Exon 1 of 7
TMEM222	NR_037577.2		n.39C>A		non_coding_transcript_exon	Exon 1 of 7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TMEM222	ENST00000374076.9	TSL:1 MANE Select	c.86C>A	p.Ala29Glu	missense	Exon 1 of 6	ENSP00000363189.4	Q9H0R3-1
TMEM222	ENST00000611517.4	TSL:1	c.86C>A	p.Ala29Glu	missense	Exon 1 of 6	ENSP00000483276.1	Q9H0R3-1
TMEM222	ENST00000608611.5	TSL:1	c.-14C>A		5_prime_UTR	Exon 1 of 6	ENSP00000476439.1	Q8TDQ4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.16e-7

AC:

AN:

1397132

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

692022

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

30578

American (AMR)

AF:

0.00

AC:

AN:

37370

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24734

East Asian (EAS)

AF:

0.00

AC:

AN:

35170

South Asian (SAS)

AF:

0.00

AC:

AN:

79004

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50208

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5612

European-Non Finnish (NFE)

AF:

9.28e-7

AC:

AN:

1077126

Other (OTH)

AF:

0.00

AC:

AN:

57330

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

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.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.098

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.014

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.42

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.75

M_CAP

Benign

0.0046

MetaRNN

Benign

0.087

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.46

PhyloP100

0.91

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-0.54

REVEL

Uncertain

0.29

Sift

Benign

0.18

Sift4G

Benign

0.73

Polyphen

0.0030

Vest4

0.30

MutPred

0.11

Gain of solvent accessibility (P = 0.0488)

MVP

0.12

MPC

0.94

ClinPred

0.86

GERP RS

3.5

PromoterAI

0.072

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

Varity_R

0.14

gMVP

0.56

Mutation Taster

=86/14

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