1-27322280-C-T

Variant names:

• chr1-27322280-C-T
• rs149234604
• ENST00000608611.5:c.-17C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000608611.5(TMEM222):​c.-17C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000215 in 1,396,682 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TMEM222 ENST00000608611.5 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.88
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28208482).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000608611.5. 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
	TMEM222	NM_032125.3	MANE Select	c.83C>T	p.Thr28Met	missense	Exon 1 of 6	NP_115501.2	Q9H0R3-1
	TMEM222	NR_037576.2		n.36C>T		non_coding_transcript_exon	Exon 1 of 7
	TMEM222	NR_037577.2		n.36C>T		non_coding_transcript_exon	Exon 1 of 7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM222	ENST00000608611.5	TSL:1	c.-17C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 6	ENSP00000476439.1	Q8TDQ4
	TMEM222	ENST00000374076.9	TSL:1 MANE Select	c.83C>T	p.Thr28Met	missense	Exon 1 of 6	ENSP00000363189.4	Q9H0R3-1
	TMEM222	ENST00000611517.4	TSL:1	c.83C>T	p.Thr28Met	missense	Exon 1 of 6	ENSP00000483276.1	Q9H0R3-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000215 AC: 3 AN: 1396682 Hom.: 0 Cov.: 31 AF XY: 0.00000434 AC XY: 3 AN XY: 691814

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

African (AFR) AF: 0.00 AC: 0 AN: 30576

American (AMR) AF: 0.00 AC: 0 AN: 37104

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24736

East Asian (EAS) AF: 0.00 AC: 0 AN: 35222

South Asian (SAS) AF: 0.0000253 AC: 2 AN: 78950

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50072

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5616

European-Non Finnish (NFE) AF: 9.28e-7 AC: 1 AN: 1077066

Other (OTH) AF: 0.00 AC: 0 AN: 57340

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0662318), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.015	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.014	T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		2.9
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.46	N
REVEL	Benign	0.12
Sift	Benign	0.052	T
Sift4G	Benign	0.079	T
Polyphen		1.0	D
Vest4		0.39
MutPred		0.26		Loss of glycosylation at T28 (P = 0.0068)
MVP		0.36
MPC		0.52
ClinPred		0.97	D
GERP RS		4.4
PromoterAI		0.043	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.12
gMVP		0.54
Mutation Taster		=71/29	polymorphism

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

Other links and lift over

dbSNP: rs149234604; hg19: chr1-27648771; COSMIC: COSV65027313; COSMIC: COSV65027313;