NM_001394961.1:c.142G>T

Variant names:

• chr12-57236597-C-A
• NM_001394961.1:c.142G>T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001394961.1(NDUFA4L2):​c.142G>T​(p.Val48Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000000701 in 1,427,320 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. V48I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: NDUFA4L2 NM_001394961.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.14

Genes affected

NDUFA4L2 (HGNC:29836): (NDUFA4 mitochondrial complex associated like 2) Predicted to be integral component of membrane. Predicted to be part of mitochondrial respiratory chain complex IV. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.964

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFA4L2	NM_001394961.1	c.142G>T	p.Val48Phe	missense_variant	Exon 2 of 4	ENST00000554503.6	NP_001381890.1
NDUFA4L2	NM_001394960.1	c.142G>T	p.Val48Phe	missense_variant	Exon 3 of 5		NP_001381889.1
NDUFA4L2	NM_020142.4	c.142G>T	p.Val48Phe	missense_variant	Exon 3 of 5		NP_064527.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFA4L2	ENST00000554503.6	c.142G>T	p.Val48Phe	missense_variant	Exon 2 of 4	1	NM_001394961.1	ENSP00000450664.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.01e-7 AC: 1 AN: 1427320 Hom.: 0 Cov.: 31 AF XY: 0.00000142 AC XY: 1 AN XY: 706120

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.13e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.65	D;D;T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.96	.;D;D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Uncertain	0.70	D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-4.6	D;D;D
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.94
MutPred		0.77		Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);
MVP		0.92
MPC		0.21
ClinPred		1.0	D
GERP RS		3.4
Varity_R		0.71
gMVP		0.71

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: chr12-57630380;