chr4-165079734-C-A

Variant names:

• chr4-165079734-C-A
• NM_001100389.2:c.740G>T

Variant summary

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

The NM_001100389.2(TMEM192):​c.740G>T​(p.Arg247Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,730 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: 0.0000027 (0 hom.)
• Consequence: TMEM192 NM_001100389.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.18

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.740G>T	p.Arg247Leu	missense_variant	Exon 6 of 6	ENST00000306480.11	NP_001093859.1
TMEM192	XM_011531718.4	c.605G>T	p.Arg202Leu	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.740G>T	p.Arg247Leu	missense_variant	Exon 6 of 6	1	NM_001100389.2	ENSP00000305069.4
TMEM192	ENST00000506087.5	c.728G>T	p.Arg243Leu	missense_variant	Exon 7 of 7	2		ENSP00000425335.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461730 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727178

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 28, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.740G>T (p.R247L) 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 740, causing the arginine (R) at amino acid position 247 to be replaced by a leucine (L). 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	Benign	0.23
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T;.
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.018	T
MetaRNN	Uncertain	0.55	D;D
MetaSVM	Benign	-0.36	T
MutationAssessor	Uncertain	2.6	M;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.8	D;D
REVEL	Benign	0.15
Sift	Uncertain	0.014	D;D
Sift4G	Uncertain	0.016	D;D
Polyphen		1.0	D;.
Vest4		0.60
MutPred		0.30		Gain of catalytic residue at R247 (P = 3e-04);.;
MVP		0.27
MPC		0.11
ClinPred		0.99	D
GERP RS		6.0
Varity_R		0.37
gMVP		0.37

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-166000886;