19-48333399-G-T

Position:

• chr19-48333399-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_018273.4(TMEM143):​c.1200C>A​(p.Asn400Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,453,198 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: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TMEM143 NM_018273.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.148

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05800447).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM143	NM_018273.4	c.1200C>A	p.Asn400Lys	missense_variant	8/8	ENST00000293261.8	NP_060743.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM143	ENST00000293261.8	c.1200C>A	p.Asn400Lys	missense_variant	8/8	1	NM_018273.4	ENSP00000293261.2
TMEM143	ENST00000377431.6	c.900C>A	p.Asn300Lys	missense_variant	6/6	1		ENSP00000366649.1
TMEM143	ENST00000435956.7	c.1095C>A	p.Asn365Lys	missense_variant	7/7	2		ENSP00000397038.2
TMEM143	ENST00000600816.1	n.687C>A		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1453198 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 722582

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: 0.00000271

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Mar 23, 2023

The c.1200C>A (p.N400K) alteration is located in exon 8 (coding exon 8) of the TMEM143 gene. This alteration results from a C to A substitution at nucleotide position 1200, causing the asparagine (N) at amino acid position 400 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	Benign	0.11
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.027	T;.;T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.50	N
LIST_S2	Benign	0.68	T;T;T
M_CAP	Benign	0.0050	T
MetaRNN	Benign	0.058	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N;.;.
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Benign	0.020
Sift	Benign	0.46	T;T;T
Sift4G	Benign	0.30	T;T;T
Polyphen		0.11	B;B;B
Vest4		0.062
MutPred		0.34		Gain of ubiquitination at N400 (P = 0.0192);.;.;
MVP		0.20
MPC		0.88
ClinPred		0.60	D
GERP RS		1.0
Varity_R		0.17
gMVP		0.097

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs944685467; hg19: chr19-48836656;