chr19-48333372-C-A

Variant names:

• chr19-48333372-C-A
• rs1280945053
• NM_018273.4:c.1227G>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_018273.4(TMEM143):​c.1227G>T​(p.Glu409Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,456,714 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E409A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TMEM143 NM_018273.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.17
• 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: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.025452703).
• BP6: Variant 19-48333372-C-A is Benign according to our data. Variant chr19-48333372-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3807922.Status of the report is criteria_provided_single_submitter, 1 stars.

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.1227G>T	p.Glu409Asp	missense	Exon 8 of 8	NP_060743.2
	TMEM143	NM_001303538.2		c.1122G>T	p.Glu374Asp	missense	Exon 7 of 7	NP_001290467.1	B4DMT0
	TMEM143	NM_001303539.2		c.1032G>T	p.Glu344Asp	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.1227G>T	p.Glu409Asp	missense	Exon 8 of 8	ENSP00000293261.2	Q96AN5-1
	TMEM143	ENST00000377431.6	TSL:1	c.927G>T	p.Glu309Asp	missense	Exon 6 of 6	ENSP00000366649.1	Q96AN5-2
	TMEM143	ENST00000948722.1		c.1224G>T	p.Glu408Asp	missense	Exon 8 of 8	ENSP00000618781.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1456714 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 724720

African (AFR) AF: 0.00 AC: 0 AN: 33440

American (AMR) AF: 0.00 AC: 0 AN: 44514

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26024

East Asian (EAS) AF: 0.00 AC: 0 AN: 39546

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85780

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53188

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108464

Other (OTH) AF: 0.00 AC: 0 AN: 60010

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely benign

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	Benign	0.073
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.14
DANN	Benign	0.97
DEOGEN2	Benign	0.027	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.025	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.14	N
PhyloP100		-2.2
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.73	N
REVEL	Benign	0.045
Sift	Benign	1.0	T
Sift4G	Benign	0.81	T
Polyphen		0.0	B
Vest4		0.037
MutPred		0.23		Loss of sheet (P = 0.0357)
MVP		0.072
MPC		0.75
ClinPred		0.25	T
GERP RS		-8.9
Varity_R		0.073
gMVP		0.097
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: rs1280945053; hg19: chr19-48836629;