chr19-48333262-G-T

Variant names:

• chr19-48333262-G-T
• rs755314000
• NM_018273.4:c.1337C>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.1337C>A​(p.Thr446Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000479 in 1,524,002 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000050 (0 hom.)
• Consequence: TMEM143 NM_018273.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.48
• 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=0.07455504).

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.1337C>A	p.Thr446Asn	missense	Exon 8 of 8	NP_060743.2
	TMEM143	NM_001303538.2		c.1232C>A	p.Thr411Asn	missense	Exon 7 of 7	NP_001290467.1	B4DMT0
	TMEM143	NM_001303539.2		c.1142C>A	p.Thr381Asn	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.1337C>A	p.Thr446Asn	missense	Exon 8 of 8	ENSP00000293261.2	Q96AN5-1
	TMEM143	ENST00000377431.6	TSL:1	c.1037C>A	p.Thr346Asn	missense	Exon 6 of 6	ENSP00000366649.1	Q96AN5-2
	TMEM143	ENST00000948722.1		c.1334C>A	p.Thr445Asn	missense	Exon 8 of 8	ENSP00000618781.1

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152214 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000192 AC: 4 AN: 208674 AF XY: 0.0000268

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000313

Gnomad OTH exome AF: 0.000206

GnomAD4 exome AF: 0.0000496 AC: 68 AN: 1371788 Hom.: 0 Cov.: 30 AF XY: 0.0000430 AC XY: 29 AN XY: 674556

African (AFR) AF: 0.00 AC: 0 AN: 31596

American (AMR) AF: 0.00 AC: 0 AN: 37476

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22000

East Asian (EAS) AF: 0.00 AC: 0 AN: 37530

South Asian (SAS) AF: 0.0000132 AC: 1 AN: 75942

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5310

European-Non Finnish (NFE) AF: 0.0000625 AC: 66 AN: 1055540

Other (OTH) AF: 0.0000179 AC: 1 AN: 55794

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152214 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74368

African (AFR) AF: 0.0000241 AC: 1 AN: 41442

American (AMR) AF: 0.000131 AC: 2 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68044

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000302

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ExAC AF: 0.00000824 AC: 1

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	Benign	0.082
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0099	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.075	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
PhyloP100		1.5
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.80	N
REVEL	Benign	0.034
Sift	Uncertain	0.012	D
Sift4G	Benign	0.13	T
Polyphen		0.66	P
Vest4		0.20
MutPred		0.19		Loss of glycosylation at T446 (P = 6e-04)
MVP		0.26
MPC		0.89
ClinPred		0.055	T
GERP RS		0.67
Varity_R		0.15
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: rs755314000; hg19: chr19-48836519;