4-55396313-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_018475.5(TMEM165):​c.124C>T​(p.Arg42Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000393 in 1,526,786 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000036 ( 0 hom. )

Consequence

TMEM165
NM_018475.5 missense

Scores

3
6
10

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.176

Publications

0 publications found
Variant links:
Genes affected
TMEM165 (HGNC:30760): (transmembrane protein 165) This gene encodes a predicted transmembrane protein with a perinuclear Golgi-like distribution in fibroblasts. Mutations in this gene are associated with the autosomal recessive disorder congenital disorder of glycosylation, type IIk. Knockdown of this gene's expression causes decreased sialylation in HEK cells and suggests this gene plays a role in terminal Golgi glycosylation. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2012]
SRD5A3-AS1 (HGNC:44138): (SRD5A3 antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 2 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 1.3658 (below the threshold of 3.09). Trascript score misZ: 0.68834 (below the threshold of 3.09). GenCC associations: The gene is linked to TMEM165-congenital disorder of glycosylation.
BP4
Computational evidence support a benign effect (MetaRNN=0.28417706).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TMEM165NM_018475.5 linkc.124C>T p.Arg42Trp missense_variant Exon 1 of 6 ENST00000381334.10 NP_060945.2 Q9HC07-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TMEM165ENST00000381334.10 linkc.124C>T p.Arg42Trp missense_variant Exon 1 of 6 1 NM_018475.5 ENSP00000370736.5 Q9HC07-1

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
152080
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000364
AC:
5
AN:
1374706
Hom.:
0
Cov.:
34
AF XY:
0.00000589
AC XY:
4
AN XY:
679402
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00
AC:
0
AN:
28680
American (AMR)
AF:
0.00
AC:
0
AN:
34850
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
24406
East Asian (EAS)
AF:
0.00
AC:
0
AN:
33254
South Asian (SAS)
AF:
0.0000129
AC:
1
AN:
77422
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
39874
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5598
European-Non Finnish (NFE)
AF:
0.00000279
AC:
3
AN:
1073482
Other (OTH)
AF:
0.0000175
AC:
1
AN:
57140
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000889), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.375
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
152080
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74286
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41416
American (AMR)
AF:
0.00
AC:
0
AN:
15274
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5170
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4830
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10604
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
314
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
68000
Other (OTH)
AF:
0.00
AC:
0
AN:
2092
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

TMEM165-congenital disorder of glycosylation Uncertain:1
Jul 03, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with TMEM165-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 42 of the TMEM165 protein (p.Arg42Trp). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.19
BayesDel_addAF
Uncertain
0.084
D
BayesDel_noAF
Benign
-0.12
CADD
Uncertain
25
DANN
Benign
0.94
DEOGEN2
Benign
0.057
.;T
Eigen
Uncertain
0.20
Eigen_PC
Benign
0.14
FATHMM_MKL
Benign
0.32
N
LIST_S2
Uncertain
0.90
D;D
M_CAP
Pathogenic
0.98
D
MetaRNN
Benign
0.28
T;T
MetaSVM
Uncertain
0.19
D
MutationAssessor
Benign
1.6
.;L
PhyloP100
0.18
PrimateAI
Pathogenic
0.92
D
PROVEAN
Benign
6.7
N;N
REVEL
Uncertain
0.35
Sift
Uncertain
0.0020
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
.;D
Vest4
0.42
MutPred
0.14
Loss of phosphorylation at S40 (P = 0.0728);Loss of phosphorylation at S40 (P = 0.0728);
MVP
0.52
MPC
1.5
ClinPred
0.62
D
GERP RS
4.2
PromoterAI
-0.14
Neutral
Varity_R
0.19
gMVP
0.51
Mutation Taster
=257/43
polymorphism

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

Other links and lift over

dbSNP: rs1036333511; hg19: chr4-56262480; API