chr1-27333980-C-T

Variant names:

• chr1-27333980-C-T
• rs774049520
• NM_032125.3:c.334C>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_032125.3(TMEM222):​c.334C>T​(p.Gln112*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TMEM222 NM_032125.3 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.56
• 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

ENSG00000304055 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-27333980-C-T is Pathogenic according to our data. Variant chr1-27333980-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 1195883.Status of the report is no_assertion_criteria_provided, 0 stars.

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.334C>T	p.Gln112*	stop_gained	Exon 4 of 6	NP_115501.2	Q9H0R3-1
	TMEM222	NR_037576.2		n.440C>T		non_coding_transcript_exon	Exon 5 of 7
	TMEM222	NR_037577.2		n.287C>T		non_coding_transcript_exon	Exon 4 of 7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM222	ENST00000374076.9	TSL:1 MANE Select	c.334C>T	p.Gln112*	stop_gained	Exon 4 of 6	ENSP00000363189.4	Q9H0R3-1
	TMEM222	ENST00000611517.4	TSL:1	c.334C>T	p.Gln112*	stop_gained	Exon 4 of 6	ENSP00000483276.1	Q9H0R3-1
	TMEM222	ENST00000608611.5	TSL:1	c.235C>T	p.Gln79*	stop_gained	Exon 4 of 6	ENSP00000476439.1	Q8TDQ4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Neurodevelopmental disorder with motor and speech delay and behavioral abnormalities (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Uncertain	0.88	D
PhyloP100		4.6
Vest4		0.32
ClinPred		1.0	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=4/196	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs774049520; hg19: chr1-27660471;