Genetic Variant TMEM222:c.-4C>G (chr1-27322194-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_032125.3(TMEM222):c.-4C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000727 in 1,389,386 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000074 ( 0 hom. )

Consequence

TMEM222
NM_032125.3 5_prime_UTR

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.20

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: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

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	Effect	Exon Rank	Protein	UniProt
TMEM222	NM_032125.3	MANE Select	c.-4C>G	5_prime_UTR	Exon 1 of 6	NP_115501.2	Q9H0R3-1
TMEM222	NR_037576.2		n.-51C>G	upstream_gene	N/A
TMEM222	NR_037577.2		n.-51C>G	upstream_gene	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TMEM222	ENST00000374076.9	TSL:1 MANE Select	c.-4C>G	5_prime_UTR	Exon 1 of 6	ENSP00000363189.4	Q9H0R3-1
TMEM222	ENST00000611517.4	TSL:1	c.-4C>G	5_prime_UTR	Exon 1 of 6	ENSP00000483276.1	Q9H0R3-1
TMEM222	ENST00000915856.1		c.-4C>G	5_prime_UTR	Exon 1 of 6	ENSP00000585915.1

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000456

AC:

AN:

65772

AF XY:

0.0000842

show subpopulations

Gnomad AFR exome

AF:

0.000260

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:

0.0000666

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000744

AC:

AN:

1237026

Hom.:

Cov.:

AF XY:

0.0000800

AC XY:

AN XY:

600104

show subpopulations

African (AFR)

AF:

0.0000779

AC:

AN:

25680

American (AMR)

AF:

0.00

AC:

AN:

15136

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17256

East Asian (EAS)

AF:

0.00

AC:

AN:

30672

South Asian (SAS)

AF:

0.00

AC:

AN:

57616

European-Finnish (FIN)

AF:

0.00

AC:

AN:

44060

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3668

European-Non Finnish (NFE)

AF:

0.0000886

AC:

AN:

993016

Other (OTH)

AF:

0.0000401

AC:

AN:

49922

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

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

AF:

0.0000591

AC:

AN:

152360

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.0000721

AC:

AN:

41586

American (AMR)

AF:

0.00

AC:

AN:

15314

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.536

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000416

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

(source)

DANN

Benign

0.81

PhyloP100

3.2

PromoterAI

0.049

Neutral

(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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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