19-48334172-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018273.4(TMEM143):c.1001A>G(p.Gln334Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,453,280 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign 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: 2.49

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26086277).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM143	NM_018273.4	c.1001A>G	p.Gln334Arg	missense_variant	7/8	ENST00000293261.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM143	ENST00000293261.8	c.1001A>G	p.Gln334Arg	missense_variant	7/8	1	NM_018273.4	P1
TMEM143	ENST00000377431.6	c.701A>G	p.Gln234Arg	missense_variant	5/6	1
TMEM143	ENST00000435956.7	c.896A>G	p.Gln299Arg	missense_variant	6/7	2
TMEM143	ENST00000600816.1	n.488A>G		non_coding_transcript_exon_variant	2/3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1453280 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 722262

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.: 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

May 05, 2023

The c.1001A>G (p.Q334R) alteration is located in exon 7 (coding exon 7) of the TMEM143 gene. This alteration results from a A to G substitution at nucleotide position 1001, causing the glutamine (Q) at amino acid position 334 to be replaced by an arginine (R). 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	Benign	0.11
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.035	T;.;T
Eigen	Benign	-0.0065
Eigen_PC	Benign	0.0040
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.78	T;T;T
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.26	T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.3	L;.;.
MutationTaster	Benign	0.72	D;D;D;D;D
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.90	N;N;N
REVEL	Benign	0.17
Sift	Benign	0.31	T;T;T
Sift4G	Benign	0.18	T;T;T
Polyphen		0.78	P;P;P
Vest4		0.42
MutPred		0.57		Gain of MoRF binding (P = 0.0106);.;.;
MVP		0.21
MPC		0.85
ClinPred		0.47	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.16
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1169067572; hg19: chr19-48837429; COSMIC: COSV53156835; COSMIC: COSV53156835;