Variant 4-165100690-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The ENST00000306480.11(TMEM192):c.377A>G(p.Tyr126Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TMEM192
ENST00000306480.11 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.36

Variant links:

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]

TMEM192 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.865

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM192	NM_001100389.2 linkuse as main transcript	c.377A>G	p.Tyr126Cys	missense_variant	3/6	ENST00000306480.11	NP_001093859.1	Q8IY95-1
TMEM192	XM_011531718.4 linkuse as main transcript	c.377A>G	p.Tyr126Cys	missense_variant	3/5		XP_011530020.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TMEM192	ENST00000306480.11 linkuse as main transcript	c.377A>G	p.Tyr126Cys	missense_variant	3/6	1	NM_001100389.2	ENSP00000305069.4	Q8IY95-1
TMEM192	ENST00000505095.1 linkuse as main transcript	c.-47A>G		5_prime_UTR_premature_start_codon_gain_variant	4/6	3		ENSP00000424590.1	D6RAZ6
TMEM192	ENST00000506087.5 linkuse as main transcript	c.365A>G	p.Tyr122Cys	missense_variant	4/7	2		ENSP00000425335.1	Q8IY95-2
TMEM192	ENST00000505095.1 linkuse as main transcript	c.-47A>G		5_prime_UTR_variant	4/6	3		ENSP00000424590.1	D6RAZ6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000401

AC:

AN:

249550

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135396

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461866

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727232

show subpopulations

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000468

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 24, 2022

The c.377A>G (p.Y126C) alteration is located in exon 3 (coding exon 3) of the TMEM192 gene. This alteration results from a A to G substitution at nucleotide position 377, causing the tyrosine (Y) at amino acid position 126 to be replaced by a cysteine (C). 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

Uncertain

0.42

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.37

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.46

T;.

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.93

D;D

M_CAP

Benign

0.025

MetaRNN

Pathogenic

0.86

D;D

MetaSVM

Uncertain

-0.14

MutationAssessor

Uncertain

2.8

M;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.60

PROVEAN

Pathogenic

-8.1

D;D

REVEL

Pathogenic

0.76

Sift

Uncertain

0.0010

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;.

Vest4

0.86

MutPred

0.56

Loss of disorder (P = 0.0825);.;

MVP

0.33

MPC

0.16

ClinPred

1.0

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.76

gMVP

0.81

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over