1-32221169-C-T

Variant names:

• chr1-32221169-C-T
• NM_019118.5:c.197G>A

Variant summary

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

The NM_019118.5(TMEM234):​c.197G>A​(p.Cys66Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,456 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. C66G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TMEM234 NM_019118.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.76
• Publications: 0 publications found

Genes affected

TMEM234 (HGNC:28837): (transmembrane protein 234) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

EIF3I (HGNC:3272): (eukaryotic translation initiation factor 3 subunit I) Contributes to translation initiation factor activity. Involved in translational initiation. Located in extracellular exosome. Part of eukaryotic translation initiation factor 3 complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019118.5. 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
	TMEM234	NM_019118.5	MANE Select	c.197G>A	p.Cys66Tyr	missense	Exon 3 of 5	NP_061991.3
	TMEM234	NM_001366191.2		c.197G>A	p.Cys66Tyr	missense	Exon 3 of 6	NP_001353120.1	Q8WY98-1
	TMEM234	NR_133634.2		n.228G>A		non_coding_transcript_exon	Exon 3 of 6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM234	ENST00000309777.11	TSL:1 MANE Select	c.197G>A	p.Cys66Tyr	missense	Exon 3 of 5	ENSP00000309792.6	Q8WY98-3
	TMEM234	ENST00000373593.5	TSL:1	c.197G>A	p.Cys66Tyr	missense	Exon 3 of 4	ENSP00000362695.1	Q8WY98-2
	TMEM234	ENST00000344461.7	TSL:1	c.197G>A	p.Cys66Tyr	missense	Exon 3 of 6	ENSP00000344021.3	Q8WY98-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461456 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726980

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44654

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86108

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53350

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111882

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.040	D
MetaRNN	Uncertain	0.74	D
MetaSVM	Uncertain	0.14	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		3.8
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Uncertain	0.48
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.99	D
Vest4		0.63
MutPred		0.58		Loss of helix (P = 0.3949)
MVP		0.62
MPC		0.81
ClinPred		0.99	D
GERP RS		4.7
PromoterAI		0.0059	Neutral
Varity_R		0.78
gMVP		0.35
Mutation Taster		=97/3	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

hg19: chr1-32686770;