4-165079758-C-A

Variant names:

• chr4-165079758-C-A
• NM_001100389.2:c.716G>T

Variant summary

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

The NM_001100389.2(TMEM192):​c.716G>T​(p.Gly239Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TMEM192 NM_001100389.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.00

Genes affected

TMEM192 (HGNC:26775): (transmembrane protein 192) Enables protein homodimerization activity. Located in several cellular components, including late endosome; lysosomal membrane; and perinuclear region of cytoplasm. [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
TMEM192	NM_001100389.2	c.716G>T	p.Gly239Val	missense_variant	Exon 6 of 6	ENST00000306480.11	NP_001093859.1
TMEM192	XM_011531718.4	c.581G>T	p.Gly194Val	missense_variant	Exon 5 of 5		XP_011530020.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM192	ENST00000306480.11	c.716G>T	p.Gly239Val	missense_variant	Exon 6 of 6	1	NM_001100389.2	ENSP00000305069.4
TMEM192	ENST00000506087.5	c.704G>T	p.Gly235Val	missense_variant	Exon 7 of 7	2		ENSP00000425335.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 01, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.716G>T (p.G239V) alteration is located in exon 6 (coding exon 6) of the TMEM192 gene. This alteration results from a G to T substitution at nucleotide position 716, causing the glycine (G) at amino acid position 239 to be replaced by a valine (V). 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	0.58
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.090	T;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Benign	0.013	T
MetaRNN	Uncertain	0.59	D;D
MetaSVM	Benign	-0.50	T
MutationAssessor	Uncertain	2.6	M;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-2.3	N;N
REVEL	Uncertain	0.58
Sift	Uncertain	0.018	D;D
Sift4G	Uncertain	0.014	D;D
Polyphen		0.98	D;.
Vest4		0.66
MutPred		0.24		Loss of ubiquitination at K237 (P = 0.048);.;
MVP		0.18
MPC		0.15
ClinPred		0.98	D
GERP RS		4.2
Varity_R		0.17
gMVP		0.52

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-166000910; COSMIC: COSV100122076;