19-48333224-A-C

Variant names:

• chr19-48333224-A-C
• rs186626048
• NM_018273.4:c.1375T>G

Variant summary

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

The NM_018273.4(TMEM143):​c.1375T>G​(p.Ser459Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000376 in 1,331,152 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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: 0.0000038 (0 hom.)
• Consequence: TMEM143 NM_018273.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.616

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=0.049318075).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM143	NM_018273.4	c.1375T>G	p.Ser459Ala	missense_variant	Exon 8 of 8	ENST00000293261.8	NP_060743.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM143	ENST00000293261.8	c.1375T>G	p.Ser459Ala	missense_variant	Exon 8 of 8	1	NM_018273.4	ENSP00000293261.2
TMEM143	ENST00000377431.6	c.1075T>G	p.Ser359Ala	missense_variant	Exon 6 of 6	1		ENSP00000366649.1
TMEM143	ENST00000435956.7	c.1270T>G	p.Ser424Ala	missense_variant	Exon 7 of 7	2		ENSP00000397038.2
TMEM143	ENST00000600816.1	n.*52T>G		downstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000376 AC: 5 AN: 1331152 Hom.: 0 Cov.: 30 AF XY: 0.00000460 AC XY: 3 AN XY: 651506

Gnomad4 AFR exome AF: 0.0000985

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: 0.00

Gnomad4 OTH exome AF: 0.0000371

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 24, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1375T>G (p.S459A) alteration is located in exon 8 (coding exon 8) of the TMEM143 gene. This alteration results from a T to G substitution at nucleotide position 1375, causing the serine (S) at amino acid position 459 to be replaced by an alanine (A). 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	0.063
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	14
DANN	Benign	0.89
DEOGEN2	Benign	0.0091	T;.;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.068	N
LIST_S2	Benign	0.19	T;T;T
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.049	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;.;.
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.31	N;N;N
REVEL	Benign	0.019
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.0010	B;B;B
Vest4		0.093
MVP		0.014
MPC		0.24
ClinPred		0.11	T
GERP RS		-0.93
Varity_R		0.24
gMVP		0.21

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

Publications

LitVar

Other links and lift over

dbSNP: rs186626048; hg19: chr19-48836481;