7-12229791-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001134232.2(TMEM106B):ā€‹c.554C>Gā€‹(p.Thr185Ser) variant causes a missense change. The variant allele was found at a frequency of 0.447 in 1,603,674 control chromosomes in the GnomAD database, including 167,361 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (ā˜…ā˜…). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: š‘“ 0.50 ( 20500 hom., cov: 33)
Exomes š‘“: 0.44 ( 146861 hom. )

Consequence

TMEM106B
NM_001134232.2 missense

Scores

1
3
14

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 5.98
Variant links:
Genes affected
TMEM106B (HGNC:22407): (transmembrane protein 106B) Enables ATPase binding activity. Involved in dendrite morphogenesis and lysosome localization. Located in endosome and lysosomal membrane. Implicated in hypomyelinating leukodystrophy. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=3.123355E-5).
BP6
Variant 7-12229791-C-G is Benign according to our data. Variant chr7-12229791-C-G is described in ClinVar as [Benign]. Clinvar id is 1168238.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.657 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TMEM106BNM_001134232.2 linkuse as main transcriptc.554C>G p.Thr185Ser missense_variant 5/8 ENST00000396668.8 NP_001127704.1 Q9NUM4A0A024R9Z1
TMEM106BNM_018374.4 linkuse as main transcriptc.554C>G p.Thr185Ser missense_variant 6/9 NP_060844.2 Q9NUM4A0A024R9Z1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TMEM106BENST00000396668.8 linkuse as main transcriptc.554C>G p.Thr185Ser missense_variant 5/81 NM_001134232.2 ENSP00000379902.3 Q9NUM4

Frequencies

GnomAD3 genomes
AF:
0.505
AC:
76690
AN:
151952
Hom.:
20473
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.664
Gnomad AMI
AF:
0.429
Gnomad AMR
AF:
0.542
Gnomad ASJ
AF:
0.440
Gnomad EAS
AF:
0.643
Gnomad SAS
AF:
0.614
Gnomad FIN
AF:
0.333
Gnomad MID
AF:
0.528
Gnomad NFE
AF:
0.413
Gnomad OTH
AF:
0.477
GnomAD3 exomes
AF:
0.491
AC:
120502
AN:
245634
Hom.:
31392
AF XY:
0.488
AC XY:
64705
AN XY:
132722
show subpopulations
Gnomad AFR exome
AF:
0.672
Gnomad AMR exome
AF:
0.590
Gnomad ASJ exome
AF:
0.436
Gnomad EAS exome
AF:
0.658
Gnomad SAS exome
AF:
0.619
Gnomad FIN exome
AF:
0.335
Gnomad NFE exome
AF:
0.411
Gnomad OTH exome
AF:
0.457
GnomAD4 exome
AF:
0.441
AC:
640722
AN:
1451604
Hom.:
146861
Cov.:
33
AF XY:
0.444
AC XY:
320863
AN XY:
722152
show subpopulations
Gnomad4 AFR exome
AF:
0.673
Gnomad4 AMR exome
AF:
0.583
Gnomad4 ASJ exome
AF:
0.436
Gnomad4 EAS exome
AF:
0.624
Gnomad4 SAS exome
AF:
0.615
Gnomad4 FIN exome
AF:
0.340
Gnomad4 NFE exome
AF:
0.413
Gnomad4 OTH exome
AF:
0.461
GnomAD4 genome
AF:
0.505
AC:
76769
AN:
152070
Hom.:
20500
Cov.:
33
AF XY:
0.507
AC XY:
37668
AN XY:
74362
show subpopulations
Gnomad4 AFR
AF:
0.664
Gnomad4 AMR
AF:
0.542
Gnomad4 ASJ
AF:
0.440
Gnomad4 EAS
AF:
0.644
Gnomad4 SAS
AF:
0.613
Gnomad4 FIN
AF:
0.333
Gnomad4 NFE
AF:
0.413
Gnomad4 OTH
AF:
0.476
Alfa
AF:
0.415
Hom.:
9729
Bravo
AF:
0.527
TwinsUK
AF:
0.416
AC:
1542
ALSPAC
AF:
0.427
AC:
1646
ESP6500AA
AF:
0.658
AC:
2897
ESP6500EA
AF:
0.417
AC:
3587
ExAC
AF:
0.490
AC:
59520
Asia WGS
AF:
0.594
AC:
2065
AN:
3478
EpiCase
AF:
0.417
EpiControl
AF:
0.420

ClinVar

Significance: Benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -
Leukodystrophy, hypomyelinating, 16 Benign:1
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabSep 10, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.15
BayesDel_addAF
Benign
-0.62
T
BayesDel_noAF
Benign
-0.52
CADD
Benign
22
DANN
Uncertain
0.98
DEOGEN2
Benign
0.021
T;T
Eigen
Benign
0.16
Eigen_PC
Uncertain
0.32
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.44
.;T
MetaRNN
Benign
0.000031
T;T
MetaSVM
Benign
-0.97
T
MutationAssessor
Benign
1.3
L;L
PrimateAI
Uncertain
0.70
T
PROVEAN
Benign
-1.8
N;N
REVEL
Benign
0.027
Sift
Benign
0.21
T;T
Sift4G
Benign
0.67
T;T
Polyphen
0.043
B;B
Vest4
0.14
MutPred
0.17
Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);
MPC
0.24
ClinPred
0.017
T
GERP RS
5.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.15
gMVP
0.47

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: rs3173615; hg19: chr7-12269417; COSMIC: COSV67543386; COSMIC: COSV67543386; API