Genetic Variant TMEM143:p.Leu313Pro (chr19-48342567-A-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_018273.4(TMEM143):c.938T>C(p.Leu313Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,460,218 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. L313R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

TMEM143
NM_018273.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.13

Publications

0 publications found

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]

TMEM143 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.789

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018273.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TMEM143	NM_018273.4	MANE Select	c.938T>C	p.Leu313Pro	missense	Exon 6 of 8	NP_060743.2
TMEM143	NM_001303538.2		c.833T>C	p.Leu278Pro	missense	Exon 5 of 7	NP_001290467.1	B4DMT0
TMEM143	NM_001303539.2		c.743T>C	p.Leu248Pro	missense	Exon 5 of 7	NP_001290468.1	B4DPF8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TMEM143	ENST00000293261.8	TSL:1 MANE Select	c.938T>C	p.Leu313Pro	missense	Exon 6 of 8	ENSP00000293261.2	Q96AN5-1
TMEM143	ENST00000377431.6	TSL:1	c.638T>C	p.Leu213Pro	missense	Exon 4 of 6	ENSP00000366649.1	Q96AN5-2
TMEM143	ENST00000948722.1		c.935T>C	p.Leu312Pro	missense	Exon 6 of 8	ENSP00000618781.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000406

AC:

AN:

246248

AF XY:

0.00000749

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000899

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000753

AC:

AN:

1460218

Hom.:

Cov.:

AF XY:

0.00000826

AC XY:

AN XY:

726444

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33468

American (AMR)

AF:

0.00

AC:

AN:

44660

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26108

East Asian (EAS)

AF:

0.00

AC:

AN:

39672

South Asian (SAS)

AF:

0.00

AC:

AN:

86196

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52298

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000989

AC:

AN:

1111706

Other (OTH)

AF:

0.00

AC:

AN:

60344

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Uncertain

0.064

BayesDel_noAF

Benign

-0.15

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.15

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.83

M_CAP

Benign

0.040

MetaRNN

Pathogenic

0.79

MetaSVM

Benign

-0.84

MutationAssessor

Benign

1.8

PhyloP100

3.1

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-1.9

REVEL

Benign

0.24

Sift

Uncertain

0.022

Sift4G

Uncertain

0.0090

Polyphen

1.0

Vest4

0.81

MutPred

0.68

Loss of stability (P = 0.0167)

MVP

0.63

MPC

0.98

ClinPred

0.79

GERP RS

4.3

Varity_R

0.71

gMVP

0.83

Mutation Taster

=54/46

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over