4-4240327-C-T

Variant names:

• chr4-4240327-C-T
• rs1717895843
• NM_001297551.2:c.392G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001297551.2(TMEM128):​c.392G>A​(p.Gly131Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000144 in 1,460,400 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: TMEM128 NM_001297551.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.80

Genes affected

TMEM128 (HGNC:28201): (transmembrane protein 128) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM128	NM_001297551.2	c.392G>A	p.Gly131Glu	missense_variant	Exon 3 of 5	ENST00000382753.5	NP_001284480.1
TMEM128	NM_001297552.2	c.392G>A	p.Gly131Glu	missense_variant	Exon 3 of 5		NP_001284481.1
TMEM128	NM_032927.4	c.320G>A	p.Gly107Glu	missense_variant	Exon 3 of 5		NP_116316.1
TMEM128	XM_005248034.4	c.392G>A	p.Gly131Glu	missense_variant	Exon 3 of 5		XP_005248091.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM128	ENST00000382753.5	c.392G>A	p.Gly131Glu	missense_variant	Exon 3 of 5	1	NM_001297551.2	ENSP00000372201.4
TMEM128	ENST00000254742.6	c.320G>A	p.Gly107Glu	missense_variant	Exon 3 of 5	1		ENSP00000254742.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1460400 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 726478

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000226

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: 0.0000162

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 15, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.320G>A (p.G107E) alteration is located in exon 3 (coding exon 3) of the TMEM128 gene. This alteration results from a G to A substitution at nucleotide position 320, causing the glycine (G) at amino acid position 107 to be replaced by a glutamic acid (E). 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	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.020	.;T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.052	D
MetaRNN	Uncertain	0.59	D;D
MetaSVM	Uncertain	0.44	D
MutationAssessor	Uncertain	2.6	.;M
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.6	N;N
REVEL	Uncertain	0.55
Sift	Benign	0.050	D;D
Sift4G	Benign	0.31	T;T
Polyphen		0.96	D;D
Vest4		0.50
MutPred		0.53		.;Loss of glycosylation at S126 (P = 0.0328);
MVP		0.71
MPC		0.57
ClinPred		0.95	D
GERP RS		4.5
Varity_R		0.21
gMVP		0.84

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: rs1717895843; hg19: chr4-4242054;