7-150793995-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001101312.2(TMEM176B):​c.281G>A​(p.Ser94Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000675 in 1,613,690 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S94R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000060 ( 0 hom. )

Consequence

TMEM176B
NM_001101312.2 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.207
Variant links:
Genes affected
TMEM176B (HGNC:29596): (transmembrane protein 176B) Predicted to be involved in negative regulation of dendritic cell differentiation. Predicted to be located in nuclear membrane. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.044212878).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TMEM176BNM_001101312.2 linkc.281G>A p.Ser94Asn missense_variant Exon 3 of 7 ENST00000326442.10 NP_001094782.1 Q3YBM2-1A0A090N7V7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TMEM176BENST00000326442.10 linkc.281G>A p.Ser94Asn missense_variant Exon 3 of 7 1 NM_001101312.2 ENSP00000318409.5 Q3YBM2-1

Frequencies

GnomAD3 genomes
AF:
0.000138
AC:
21
AN:
152188
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00105
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000771
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
GnomAD3 exomes
AF:
0.0000878
AC:
22
AN:
250550
Hom.:
0
AF XY:
0.000118
AC XY:
16
AN XY:
135356
show subpopulations
Gnomad AFR exome
AF:
0.0000616
Gnomad AMR exome
AF:
0.000145
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000381
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000796
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000602
AC:
88
AN:
1461384
Hom.:
0
Cov.:
30
AF XY:
0.0000674
AC XY:
49
AN XY:
727016
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.000112
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00149
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000171
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.000138
AC:
21
AN:
152306
Hom.:
0
Cov.:
32
AF XY:
0.000228
AC XY:
17
AN XY:
74460
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00105
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000773
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000282
Hom.:
0
Bravo
AF:
0.000136
ExAC
AF:
0.0000988
AC:
12
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Dec 21, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.281G>A (p.S94N) alteration is located in exon 3 (coding exon 2) of the TMEM176B gene. This alteration results from a G to A substitution at nucleotide position 281, causing the serine (S) at amino acid position 94 to be replaced by an asparagine (N). 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
-0.59
T
BayesDel_noAF
Benign
-0.77
CADD
Benign
4.5
DANN
Benign
0.87
DEOGEN2
Benign
0.016
T;T;T;T;T
Eigen
Benign
-0.74
Eigen_PC
Benign
-0.69
FATHMM_MKL
Benign
0.014
N
LIST_S2
Benign
0.26
.;.;.;T;.
M_CAP
Benign
0.0048
T
MetaRNN
Benign
0.044
T;T;T;T;T
MetaSVM
Benign
-0.95
T
MutationAssessor
Benign
0.34
N;N;N;N;N
PrimateAI
Benign
0.33
T
PROVEAN
Benign
-0.22
N;N;N;N;N
REVEL
Benign
0.061
Sift
Benign
0.53
T;T;T;T;T
Sift4G
Benign
0.31
T;T;T;T;T
Polyphen
0.077
B;B;B;B;B
Vest4
0.080
MutPred
0.46
Loss of glycosylation at S94 (P = 0.08);Loss of glycosylation at S94 (P = 0.08);Loss of glycosylation at S94 (P = 0.08);Loss of glycosylation at S94 (P = 0.08);Loss of glycosylation at S94 (P = 0.08);
MVP
0.42
MPC
0.045
ClinPred
0.028
T
GERP RS
3.0
Varity_R
0.034
gMVP
0.21

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: rs770220387; hg19: chr7-150491083; COSMIC: COSV58441176; API