1-27322283-C-G

Variant names:

• chr1-27322283-C-G
• rs1034847273
• NM_032125.3:c.86C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032125.3(TMEM222):​c.86C>G​(p.Ala29Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000258 in 1,549,524 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TMEM222 NM_032125.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.914
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07221469).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM222	NM_032125.3	MANE Select	c.86C>G	p.Ala29Gly	missense	Exon 1 of 6	NP_115501.2	Q9H0R3-1
	TMEM222	NR_037576.2		n.39C>G		non_coding_transcript_exon	Exon 1 of 7
	TMEM222	NR_037577.2		n.39C>G		non_coding_transcript_exon	Exon 1 of 7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM222	ENST00000374076.9	TSL:1 MANE Select	c.86C>G	p.Ala29Gly	missense	Exon 1 of 6	ENSP00000363189.4	Q9H0R3-1
	TMEM222	ENST00000611517.4	TSL:1	c.86C>G	p.Ala29Gly	missense	Exon 1 of 6	ENSP00000483276.1	Q9H0R3-1
	TMEM222	ENST00000608611.5	TSL:1	c.-14C>G		5_prime_UTR	Exon 1 of 6	ENSP00000476439.1	Q8TDQ4

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152274 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1397132 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 692022

African (AFR) AF: 0.0000654 AC: 2 AN: 30578

American (AMR) AF: 0.00 AC: 0 AN: 37370

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24734

East Asian (EAS) AF: 0.00 AC: 0 AN: 35170

South Asian (SAS) AF: 0.00 AC: 0 AN: 79004

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50208

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5612

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1077126

Other (OTH) AF: 0.00 AC: 0 AN: 57330

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152392 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74528

African (AFR) AF: 0.0000481 AC: 2 AN: 41596

American (AMR) AF: 0.00 AC: 0 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.012	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.0028	T
MetaRNN	Benign	0.072	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.46	N
PhyloP100		0.91
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.58	N
REVEL	Benign	0.26
Sift	Benign	0.33	T
Sift4G	Benign	0.67	T
Polyphen		0.0010	B
Vest4		0.13
MutPred		0.15		Gain of loop (P = 0.0045)
MVP		0.13
MPC		0.34
ClinPred		0.16	T
GERP RS		3.5
PromoterAI		-0.10	Neutral
Varity_R		0.080
gMVP		0.48
Mutation Taster		=87/13	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: rs1034847273; hg19: chr1-27648774;