Variant 4-165103029-T-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The ENST00000306480.11(TMEM192):c.95A>T(p.His32Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000309 in 1,613,140 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 30)

Exomes 𝑓: 0.00033 ( 0 hom. )

Consequence

TMEM192
ENST00000306480.11 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.23

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1541611).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM192	NM_001100389.2 linkuse as main transcript	c.95A>T	p.His32Leu	missense_variant	2/6	ENST00000306480.11	NP_001093859.1	Q8IY95-1
TMEM192	XM_011531718.4 linkuse as main transcript	c.95A>T	p.His32Leu	missense_variant	2/5		XP_011530020.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TMEM192	ENST00000306480.11 linkuse as main transcript	c.95A>T	p.His32Leu	missense_variant	2/6	1	NM_001100389.2	ENSP00000305069.4	Q8IY95-1
TMEM192	ENST00000506087.5 linkuse as main transcript	c.83A>T	p.His28Leu	missense_variant	3/7	2		ENSP00000425335.1	Q8IY95-2
TMEM192	ENST00000505095.1 linkuse as main transcript	c.-329A>T		5_prime_UTR_variant	3/6	3		ENSP00000424590.1	D6RAZ6

Frequencies

GnomAD3 genomes

AF:

0.0000924

AC:

AN:

151584

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000116

AC:

AN:

249356

Hom.:

AF XY:

0.000140

AC XY:

AN XY:

135300

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:

0.000256

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000331

AC:

484

AN:

1461440

Hom.:

Cov.:

AF XY:

0.000303

AC XY:

220

AN XY:

727042

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.000427

Gnomad4 OTH exome

AF:

0.000133

GnomAD4 genome

AF:

0.0000923

AC:

AN:

151700

Hom.:

Cov.:

AF XY:

0.0000540

AC XY:

AN XY:

74098

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000178

Hom.:

Bravo

AF:

0.000110

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000362

AC:

ExAC

AF:

0.0000827

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000474

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

Jan 10, 2022

The c.95A>T (p.H32L) alteration is located in exon 2 (coding exon 2) of the TMEM192 gene. This alteration results from a A to T substitution at nucleotide position 95, causing the histidine (H) at amino acid position 32 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

0.092

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.17

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.19

T;.

Eigen

Benign

-0.016

Eigen_PC

Benign

0.027

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.53

T;T

M_CAP

Benign

0.012

MetaRNN

Benign

0.15

T;T

MetaSVM

Benign

-0.48

MutationAssessor

Uncertain

2.5

M;.

MutationTaster

Benign

0.70

D;D

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-2.9

D;D

REVEL

Benign

0.14

Sift

Uncertain

0.0090

D;D

Sift4G

Uncertain

0.011

D;D

Polyphen

0.33

B;.

Vest4

0.46

MVP

0.19

MPC

0.021

ClinPred

0.25

GERP RS

4.9

Varity_R

0.22

gMVP

0.56

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

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