19-48333372-C-A

Variant names:

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

Variant summary

Our verdict is Likely benign. Variant got -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. 15/21 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

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 -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 id is 3807922.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM143	NM_018273.4	c.1227G>T	p.Glu409Asp	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.1227G>T	p.Glu409Asp	missense_variant	Exon 8 of 8	1	NM_018273.4	ENSP00000293261.2
TMEM143	ENST00000377431.6	c.927G>T	p.Glu309Asp	missense_variant	Exon 6 of 6	1		ENSP00000366649.1
TMEM143	ENST00000435956.7	c.1122G>T	p.Glu374Asp	missense_variant	Exon 7 of 7	2		ENSP00000397038.2
TMEM143	ENST00000600816.1	n.714G>T		non_coding_transcript_exon_variant	Exon 3 of 3	2

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Jan 01, 2025

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

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;.;T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.66	T;T;T
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.025	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.14	N;.;.
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.73	N;N;N
REVEL	Benign	0.045
Sift	Benign	1.0	T;T;T
Sift4G	Benign	0.81	T;T;T
Polyphen		0.0	B;B;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

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-48836629;