19-48333295-C-T

Variant names:

• chr19-48333295-C-T
• rs1326672438
• NM_018273.4:c.1304G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018273.4(TMEM143):​c.1304G>A​(p.Gly435Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000021 in 1,426,452 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G435A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TMEM143 NM_018273.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.901
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07611853).

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.1304G>A	p.Gly435Asp	missense	Exon 8 of 8	NP_060743.2
	TMEM143	NM_001303538.2		c.1199G>A	p.Gly400Asp	missense	Exon 7 of 7	NP_001290467.1	B4DMT0
	TMEM143	NM_001303539.2		c.1109G>A	p.Gly370Asp	missense	Exon 7 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.1304G>A	p.Gly435Asp	missense	Exon 8 of 8	ENSP00000293261.2	Q96AN5-1
	TMEM143	ENST00000377431.6	TSL:1	c.1004G>A	p.Gly335Asp	missense	Exon 6 of 6	ENSP00000366649.1	Q96AN5-2
	TMEM143	ENST00000948722.1		c.1301G>A	p.Gly434Asp	missense	Exon 8 of 8	ENSP00000618781.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000210 AC: 3 AN: 1426452 Hom.: 0 Cov.: 30 AF XY: 0.00000424 AC XY: 3 AN XY: 707722

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32608

American (AMR) AF: 0.00 AC: 0 AN: 41424

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24688

East Asian (EAS) AF: 0.0000258 AC: 1 AN: 38830

South Asian (SAS) AF: 0.00 AC: 0 AN: 83160

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52368

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5622

European-Non Finnish (NFE) AF: 9.18e-7 AC: 1 AN: 1089336

Other (OTH) AF: 0.0000171 AC: 1 AN: 58416

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0482410), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.015	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.076	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.90
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.64	N
REVEL	Benign	0.022
Sift	Benign	0.11	T
Sift4G	Benign	0.30	T
Polyphen		0.52	P
Vest4		0.15
MutPred		0.28		Gain of solvent accessibility (P = 0.0638)
MVP		0.17
MPC		1.0
ClinPred		0.45	T
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.11
gMVP		0.26
Mutation Taster		=95/5	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: rs1326672438; hg19: chr19-48836552; COSMIC: COSV99507139; COSMIC: COSV99507139;