chr4-165085679-C-A

Variant names:

• chr4-165085679-C-A
• rs553668773
• NM_001100389.2:c.584G>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001100389.2(TMEM192):​c.584G>T​(p.Arg195Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000693 in 1,444,012 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R195Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TMEM192 NM_001100389.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0630

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08003983).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM192	NM_001100389.2	c.584G>T	p.Arg195Leu	missense_variant	Exon 5 of 6	ENST00000306480.11	NP_001093859.1
TMEM192	XM_011531718.4	c.449G>T	p.Arg150Leu	missense_variant	Exon 4 of 5		XP_011530020.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM192	ENST00000306480.11	c.584G>T	p.Arg195Leu	missense_variant	Exon 5 of 6	1	NM_001100389.2	ENSP00000305069.4
TMEM192	ENST00000506087.5	c.572G>T	p.Arg191Leu	missense_variant	Exon 6 of 7	2		ENSP00000425335.1
TMEM192	ENST00000505095.1	c.161G>T	p.Arg54Leu	missense_variant	Exon 6 of 6	3		ENSP00000424590.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000418 AC: 1 AN: 239382 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 129620

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000577

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.93e-7 AC: 1 AN: 1444012 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 718522

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	6.3
DANN	Benign	0.29
DEOGEN2	Benign	0.046	T;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.076	N
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.080	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M;.;.
PrimateAI	Benign	0.19	T
PROVEAN	Benign	0.19	N;N;N
REVEL	Benign	0.13
Sift	Benign	0.64	T;T;T
Sift4G	Benign	0.47	T;T;.
Polyphen		0.71	P;.;.
Vest4		0.50
MutPred		0.38		Loss of methylation at K193 (P = 0.0548);.;.;
MVP		0.040
MPC		0.034
ClinPred		0.99	D
GERP RS		0.20
Varity_R		0.027
gMVP		0.24

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

LitVar

Other links and lift over

dbSNP: rs553668773; hg19: chr4-166006831; COSMIC: COSV60585545;