4-165103015-G-C

Variant summary

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

The ENST00000306480.11(TMEM192):ā€‹c.109C>Gā€‹(p.His37Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000961 in 1,613,472 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. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.00012 ( 0 hom., cov: 31)
Exomes š‘“: 0.000094 ( 0 hom. )

Consequence

TMEM192
ENST00000306480.11 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.65
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]

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=0.1909807).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TMEM192NM_001100389.2 linkuse as main transcriptc.109C>G p.His37Asp missense_variant 2/6 ENST00000306480.11 NP_001093859.1 Q8IY95-1
TMEM192XM_011531718.4 linkuse as main transcriptc.109C>G p.His37Asp missense_variant 2/5 XP_011530020.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TMEM192ENST00000306480.11 linkuse as main transcriptc.109C>G p.His37Asp missense_variant 2/61 NM_001100389.2 ENSP00000305069.4 Q8IY95-1
TMEM192ENST00000505095.1 linkuse as main transcriptc.-315C>G 5_prime_UTR_premature_start_codon_gain_variant 3/63 ENSP00000424590.1 D6RAZ6
TMEM192ENST00000506087.5 linkuse as main transcriptc.97C>G p.His33Asp missense_variant 3/72 ENSP00000425335.1 Q8IY95-2
TMEM192ENST00000505095.1 linkuse as main transcriptc.-315C>G 5_prime_UTR_variant 3/63 ENSP00000424590.1 D6RAZ6

Frequencies

GnomAD3 genomes
AF:
0.000118
AC:
18
AN:
152014
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0000242
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000459
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:
0.000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000441
AC:
11
AN:
249360
Hom.:
0
AF XY:
0.0000517
AC XY:
7
AN XY:
135310
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000290
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:
0.0000883
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000937
AC:
137
AN:
1461458
Hom.:
0
Cov.:
30
AF XY:
0.0000798
AC XY:
58
AN XY:
727044
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000896
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:
0.000111
Gnomad4 OTH exome
AF:
0.000166
GnomAD4 genome
AF:
0.000118
AC:
18
AN:
152014
Hom.:
0
Cov.:
31
AF XY:
0.0000943
AC XY:
7
AN XY:
74222
show subpopulations
Gnomad4 AFR
AF:
0.0000242
Gnomad4 AMR
AF:
0.000459
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000180
Hom.:
0
Bravo
AF:
0.000106
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000121
AC:
1
ExAC
AF:
0.0000496
AC:
6
EpiCase
AF:
0.000164
EpiControl
AF:
0.000119

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 submitterclinical testingAmbry GeneticsOct 27, 2023The c.109C>G (p.H37D) alteration is located in exon 2 (coding exon 2) of the TMEM192 gene. This alteration results from a C to G substitution at nucleotide position 109, causing the histidine (H) at amino acid position 37 to be replaced by an aspartic acid (D). 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
0.12
BayesDel_addAF
Benign
-0.20
T
BayesDel_noAF
Benign
-0.31
CADD
Benign
17
DANN
Benign
0.95
DEOGEN2
Benign
0.022
T;.
Eigen
Benign
-0.18
Eigen_PC
Benign
-0.15
FATHMM_MKL
Uncertain
0.89
D
LIST_S2
Benign
0.75
T;T
M_CAP
Benign
0.0065
T
MetaRNN
Benign
0.19
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Uncertain
2.4
M;.
MutationTaster
Benign
0.98
N;N
PrimateAI
Benign
0.46
T
PROVEAN
Benign
-0.60
N;N
REVEL
Benign
0.085
Sift
Benign
0.28
T;T
Sift4G
Benign
0.21
T;T
Polyphen
0.59
P;.
Vest4
0.48
MVP
0.16
MPC
0.038
ClinPred
0.12
T
GERP RS
3.7
Varity_R
0.11
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.

Other links and lift over

dbSNP: rs377055237; hg19: chr4-166024167; API