12-108591972-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_181724.3(TMEM119):​c.412G>A​(p.Val138Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000223 in 1,613,148 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. V138A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

TMEM119
NM_181724.3 missense

Scores

4
11
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.27
Variant links:
Genes affected
TMEM119 (HGNC:27884): (transmembrane protein 119) Involved in positive regulation of bone mineralization; positive regulation of osteoblast differentiation; and positive regulation of osteoblast proliferation. Located in plasma membrane. [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 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TMEM119NM_181724.3 linkc.412G>A p.Val138Met missense_variant Exon 2 of 2 ENST00000392806.4 NP_859075.2 Q4V9L6
TMEM119XM_011538271.3 linkc.412G>A p.Val138Met missense_variant Exon 3 of 3 XP_011536573.1 Q4V9L6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TMEM119ENST00000392806.4 linkc.412G>A p.Val138Met missense_variant Exon 2 of 2 1 NM_181724.3 ENSP00000376553.3 Q4V9L6
TMEM119ENST00000549031.1 linkc.412G>A p.Val138Met missense_variant Exon 3 of 3 4 ENSP00000448583.1 F8VS22

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152150
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000121
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000203
AC:
5
AN:
246554
Hom.:
0
AF XY:
0.0000150
AC XY:
2
AN XY:
133776
show subpopulations
Gnomad AFR exome
AF:
0.000128
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000328
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000181
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000212
AC:
31
AN:
1460998
Hom.:
0
Cov.:
30
AF XY:
0.0000220
AC XY:
16
AN XY:
726798
show subpopulations
Gnomad4 AFR exome
AF:
0.0000598
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000243
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000329
AC:
5
AN:
152150
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74326
show subpopulations
Gnomad4 AFR
AF:
0.000121
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:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000658
Hom.:
0
Bravo
AF:
0.0000340
ExAC
AF:
0.0000165
AC:
2

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Aug 05, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.412G>A (p.V138M) alteration is located in exon 2 (coding exon 1) of the TMEM119 gene. This alteration results from a G to A substitution at nucleotide position 412, causing the valine (V) at amino acid position 138 to be replaced by a methionine (M). 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
Pathogenic
0.84
BayesDel_addAF
Uncertain
0.033
T
BayesDel_noAF
Uncertain
0.050
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Benign
0.17
T;.
Eigen
Pathogenic
0.71
Eigen_PC
Uncertain
0.66
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.86
D;D
M_CAP
Benign
0.078
D
MetaRNN
Uncertain
0.72
D;D
MetaSVM
Uncertain
-0.17
T
MutationAssessor
Benign
1.6
L;.
PrimateAI
Uncertain
0.76
T
PROVEAN
Uncertain
-2.9
D;D
REVEL
Uncertain
0.39
Sift
Uncertain
0.0020
D;D
Sift4G
Pathogenic
0.0
D;.
Polyphen
1.0
D;.
Vest4
0.81
MVP
0.56
MPC
0.59
ClinPred
0.88
D
GERP RS
4.5
Varity_R
0.69
gMVP
0.71

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: rs770636300; hg19: chr12-108985748; API