1-27322234-C-T

Variant names:

• chr1-27322234-C-T
• rs771255804
• NM_032125.3:c.37C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_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. 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.87

Genes affected

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

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23114008).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM222	NM_032125.3	c.37C>T	p.Pro13Ser	missense_variant	Exon 1 of 6	ENST00000374076.9	NP_115501.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM222	ENST00000374076.9	c.37C>T	p.Pro13Ser	missense_variant	Exon 1 of 6	1	NM_032125.3	ENSP00000363189.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000161 AC: 21 AN: 1304150 Hom.: 0 Cov.: 31 AF XY: 0.0000156 AC XY: 10 AN XY: 639454

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000472

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000184

Gnomad4 OTH exome AF: 0.0000189

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000856 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Aug 30, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.37C>T (p.P13S) alteration is located in exon 1 (coding exon 1) of the TMEM222 gene. This alteration results from a C to T substitution at nucleotide position 37, causing the proline (P) at amino acid position 13 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Uncertain	0.048	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.011	T;T
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.75	T;.
M_CAP	Benign	0.0028	T
MetaRNN	Benign	0.23	T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.69	N;N
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.050	.;N
REVEL	Benign	0.10
Sift	Benign	0.090	.;T
Sift4G	Benign	0.19	T;T
Polyphen		0.95	P;P
Vest4		0.40
MutPred		0.16		Loss of catalytic residue at P13 (P = 0.0058);Loss of catalytic residue at P13 (P = 0.0058);
MVP		0.40
MPC		0.38
ClinPred		0.49	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.6
Varity_R		0.080
gMVP		0.75

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

LitVar

Other links and lift over

dbSNP: rs771255804; hg19: chr1-27648725;