chr19-48334133-G-T

Position:

• chr19-48334133-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_018273.4(TMEM143):​c.1040C>A​(p.Thr347Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000687 in 1,455,370 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 (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TMEM143 NM_018273.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.34

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.78

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM143	NM_018273.4	c.1040C>A	p.Thr347Lys	missense_variant	7/8	ENST00000293261.8	NP_060743.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM143	ENST00000293261.8	c.1040C>A	p.Thr347Lys	missense_variant	7/8	1	NM_018273.4	ENSP00000293261.2
TMEM143	ENST00000377431.6	c.740C>A	p.Thr247Lys	missense_variant	5/6	1		ENSP00000366649.1
TMEM143	ENST00000435956.7	c.935C>A	p.Thr312Lys	missense_variant	6/7	2		ENSP00000397038.2
TMEM143	ENST00000600816.1	n.527C>A		non_coding_transcript_exon_variant	2/3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455370 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 723632

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 23, 2023

The c.1040C>A (p.T347K) alteration is located in exon 7 (coding exon 7) of the TMEM143 gene. This alteration results from a C to A substitution at nucleotide position 1040, causing the threonine (T) at amino acid position 347 to be replaced by a lysine (K). 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	0.91
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T;.;T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.85	D;D;D
M_CAP	Benign	0.042	D
MetaRNN	Pathogenic	0.78	D;D;D
MetaSVM	Benign	-0.56	T
MutationAssessor	Uncertain	2.1	M;.;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-2.6	D;D;D
REVEL	Uncertain	0.35
Sift	Uncertain	0.021	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.99	D;D;D
Vest4		0.88
MutPred		0.38		Gain of solvent accessibility (P = 0.0044);.;.;
MVP		0.56
MPC		0.96
ClinPred		0.98	D
GERP RS		4.0
Varity_R		0.51
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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

Other links and lift over

dbSNP: rs768613206; hg19: chr19-48837390; COSMIC: COSV99507057; COSMIC: COSV99507057;