19-48342567-A-C

Variant names:

• chr19-48342567-A-C
• rs1163878914
• NM_018273.4:c.938T>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_018273.4(TMEM143):​c.938T>G​(p.Leu313Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,218 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. L313P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TMEM143 NM_018273.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.13
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM143	NM_018273.4	MANE Select	c.938T>G	p.Leu313Arg	missense	Exon 6 of 8	NP_060743.2
	TMEM143	NM_001303538.2		c.833T>G	p.Leu278Arg	missense	Exon 5 of 7	NP_001290467.1	B4DMT0
	TMEM143	NM_001303539.2		c.743T>G	p.Leu248Arg	missense	Exon 5 of 7	NP_001290468.1	B4DPF8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM143	ENST00000293261.8	TSL:1 MANE Select	c.938T>G	p.Leu313Arg	missense	Exon 6 of 8	ENSP00000293261.2	Q96AN5-1
	TMEM143	ENST00000377431.6	TSL:1	c.638T>G	p.Leu213Arg	missense	Exon 4 of 6	ENSP00000366649.1	Q96AN5-2
	TMEM143	ENST00000948722.1		c.935T>G	p.Leu312Arg	missense	Exon 6 of 8	ENSP00000618781.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460218 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 726444

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.00 AC: 0 AN: 86196

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52298

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111706

Other (OTH) AF: 0.00 AC: 0 AN: 60344

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Uncertain	0.077	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Benign	0.094
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.025	D
MetaRNN	Uncertain	0.74	D
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.8	L
PhyloP100		3.1
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.28
Sift	Benign	0.031	D
Sift4G	Benign	0.065	T
Polyphen		0.26	B
Vest4		0.85
MutPred		0.72		Gain of methylation at L313 (P = 0.0073)
MVP		0.54
MPC		0.36
ClinPred		0.74	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.50
gMVP		0.77
Mutation Taster		=69/31	polymorphism

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

Other links and lift over

dbSNP: rs1163878914; hg19: chr19-48845824;