NM_032125.3:c.403C>A

Variant names:

• chr1-27334049-C-A
• rs753514574
• NM_032125.3:c.403C>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_032125.3(TMEM222):​c.403C>A​(p.Arg135Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,156 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R135C) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: TMEM222 NM_032125.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.86

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.82

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM222	NM_032125.3	c.403C>A	p.Arg135Ser	missense_variant	Exon 4 of 6	ENST00000374076.9	NP_115501.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM222	ENST00000374076.9	c.403C>A	p.Arg135Ser	missense_variant	Exon 4 of 6	1	NM_032125.3	ENSP00000363189.4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152156 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

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 Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152156 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74328

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T;T;T;T;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.95	D;.;D;D;D
M_CAP	Benign	0.024	T
MetaRNN	Pathogenic	0.82	D;D;D;D;D
MetaSVM	Uncertain	0.27	D
MutationAssessor	Pathogenic	3.4	M;M;.;.;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-5.4	.;D;.;.;D
REVEL	Uncertain	0.64
Sift	Uncertain	0.0020	.;D;.;.;D
Sift4G	Uncertain	0.0040	D;D;D;D;D
Polyphen		0.98	D;D;.;.;.
Vest4		0.89
MutPred		0.67		Loss of helix (P = 0.0444);Loss of helix (P = 0.0444);.;.;.;
MVP		0.35
MPC		1.1
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.90
gMVP		0.87

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: rs753514574; hg19: chr1-27660540;