X-119871927-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3

The NM_004541.4(NDUFA1):c.16C>T(p.Leu6Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,097,771 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000055 (0 hom. 2 hem.)
• Consequence: NDUFA1 NM_004541.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.45

Genes affected

NDUFA1 (HGNC:7683): (NADH:ubiquinone oxidoreductase subunit A1) The human NDUFA1 gene codes for an essential component of complex I of the respiratory chain, which transfers electrons from NADH to ubiquinone. It has been noted that the N-terminal hydrophobic domain has the potential to be folded into an alpha-helix spanning the inner mitochondrial membrane with a C-terminal hydrophilic domain interacting with globular subunits of complex I. The highly conserved two-domain structure suggests that this feature is critical for the protein function and might act as an anchor for the NADH:ubiquinone oxidoreductase complex at the inner mitochondrial membrane. However, the NDUFA1 peptide is one of about 31 components of the "hydrophobic protein" (HP) fraction of complex I which is involved in proton translocation. Thus the NDUFA1 peptide may also participate in that function. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.77

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NDUFA1	NM_004541.4	c.16C>T	p.Leu6Phe	missense_variant	1/3	ENST00000371437.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NDUFA1	ENST00000371437.5	c.16C>T	p.Leu6Phe	missense_variant	1/3	1	NM_004541.4	P1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 0.00000547 AC: 6 AN: 1097771 Hom.: 0 Cov.: 31 AF XY: 0.00000551 AC XY: 2 AN XY: 363131

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: 0.00000713

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

NDUFA1-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 21, 2023

The NDUFA1 c.16C>T variant is predicted to result in the amino acid substitution p.Leu6Phe. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Uncertain	0.063	D
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.48	T
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.68
Sift	Benign	0.088	T
Sift4G	Benign	0.079	T
Polyphen		1.0	D
Vest4		0.41
MutPred		0.67		Gain of sheet (P = 0.1945);
MVP		0.83
MPC		1.9
ClinPred		0.99	D
GERP RS		3.6
Varity_R		0.70
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1367830417; hg19: chrX-119005890; COSMIC: COSV65097991; COSMIC: COSV65097991;