19-54106819-C-G

Variant names:

• chr19-54106819-C-G
• rs200318289
• NM_004542.4:c.172C>G

Variant summary

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

The NM_004542.4(NDUFA3):​c.172C>G​(p.Arg58Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,442 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R58C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NDUFA3 NM_004542.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.336
• Publications: 0 publications found

Genes affected

NDUFA3 (HGNC:7686): (NADH:ubiquinone oxidoreductase subunit A3) Involved in mitochondrial respiratory chain complex I assembly. Located in mitochondrion. Part of mitochondrial respiratory chain complex I. [provided by Alliance of Genome Resources, Apr 2022]

TFPT (HGNC:13630): (TCF3 fusion partner) Predicted to enable DNA binding activity and protein kinase binding activity. Involved in apoptotic signaling pathway. Located in nucleoplasm. Part of Ino80 complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004542.4. 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
	NDUFA3	NM_004542.4	MANE Select	c.172C>G	p.Arg58Gly	missense	Exon 4 of 4	NP_004533.1	Q6FGG4
	TFPT	NM_013342.4	MANE Select	c.*231G>C		downstream_gene	N/A	NP_037474.1	P0C1Z6-1
	TFPT	NM_001321792.2		c.*231G>C		downstream_gene	N/A	NP_001308721.1	P0C1Z6-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFA3	ENST00000485876.6	TSL:1 MANE Select	c.172C>G	p.Arg58Gly	missense	Exon 4 of 4	ENSP00000418438.1	O95167
	NDUFA3	ENST00000451517.5	TSL:1	n.*81C>G		non_coding_transcript_exon	Exon 5 of 5	ENSP00000410453.1	F2Z2C6
	NDUFA3	ENST00000484103.1	TSL:1	n.399C>G		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000121 AC: 3 AN: 248726 AF XY: 0.0000223

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000164

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460442 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726472

African (AFR) AF: 0.00 AC: 0 AN: 33426

American (AMR) AF: 0.00 AC: 0 AN: 44536

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26078

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39664

South Asian (SAS) AF: 0.00 AC: 0 AN: 86038

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53082

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111508

Other (OTH) AF: 0.00 AC: 0 AN: 60348

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	0.050
CADD	Benign	16
DANN	Uncertain	0.98
Eigen	Benign	0.17
Eigen_PC	Benign	0.058
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Benign	0.029	D
MetaRNN	Uncertain	0.44	T
MetaSVM	Benign	-0.55	T
PhyloP100		0.34
PROVEAN	Pathogenic	-9.0	D
REVEL	Pathogenic	0.67
Vest4		0.29
MutPred		0.26		Gain of MoRF binding (P = 0.0025)
MVP		0.39
ClinPred		0.85	D
GERP RS		1.4
Varity_R		0.85
Mutation Taster		=64/36	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: rs200318289; hg19: chr19-54610126;