19-48333372-C-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_018273.4(TMEM143):​c.1227G>T​(p.Glu409Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,456,714 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 Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E409A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

TMEM143
NM_018273.4 missense

Scores

19

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -2.17
Variant links:
Genes affected
TMEM143 (HGNC:25603): (transmembrane protein 143) Predicted to act upstream of or within hematopoietic progenitor cell differentiation. Located in mitochondrion. [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 -4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.025452703).
BP6
Variant 19-48333372-C-A is Benign according to our data. Variant chr19-48333372-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 3807922.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TMEM143NM_018273.4 linkc.1227G>T p.Glu409Asp missense_variant Exon 8 of 8 ENST00000293261.8 NP_060743.2 Q96AN5-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TMEM143ENST00000293261.8 linkc.1227G>T p.Glu409Asp missense_variant Exon 8 of 8 1 NM_018273.4 ENSP00000293261.2 Q96AN5-1
TMEM143ENST00000377431.6 linkc.927G>T p.Glu309Asp missense_variant Exon 6 of 6 1 ENSP00000366649.1 Q96AN5-2
TMEM143ENST00000435956.7 linkc.1122G>T p.Glu374Asp missense_variant Exon 7 of 7 2 ENSP00000397038.2 B4DMT0
TMEM143ENST00000600816.1 linkn.714G>T non_coding_transcript_exon_variant Exon 3 of 3 2

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.86e-7
AC:
1
AN:
1456714
Hom.:
0
Cov.:
30
AF XY:
0.00000138
AC XY:
1
AN XY:
724720
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000117
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Benign:1
Jan 01, 2025
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.073
BayesDel_addAF
Benign
-0.37
T
BayesDel_noAF
Benign
-0.77
CADD
Benign
0.14
DANN
Benign
0.97
DEOGEN2
Benign
0.027
T;.;T
Eigen
Benign
-1.7
Eigen_PC
Benign
-1.7
FATHMM_MKL
Benign
0.013
N
LIST_S2
Benign
0.66
T;T;T
M_CAP
Benign
0.0035
T
MetaRNN
Benign
0.025
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
-0.14
N;.;.
PrimateAI
Benign
0.41
T
PROVEAN
Benign
-0.73
N;N;N
REVEL
Benign
0.045
Sift
Benign
1.0
T;T;T
Sift4G
Benign
0.81
T;T;T
Polyphen
0.0
B;B;B
Vest4
0.037
MutPred
0.23
Loss of sheet (P = 0.0357);.;.;
MVP
0.072
MPC
0.75
ClinPred
0.25
T
GERP RS
-8.9
Varity_R
0.073
gMVP
0.097

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-48836629; API