6-96897795-C-T

Variant names:

• chr6-96897795-C-T
• NM_014165.4:c.7G>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM5

The NM_014165.4(NDUFAF4):​c.7G>A​(p.Ala3Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,818 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. A3P) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NDUFAF4 NM_014165.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.97

Genes affected

NDUFAF4 (HGNC:21034): (NADH:ubiquinone oxidoreductase complex assembly factor 4) NADH:ubiquinone oxidoreductase (complex I) catalyzes the transfer of electrons from NADH to ubiquinone (coenzyme Q) in the first step of the mitochondrial respiratory chain, resulting in the translocation of protons across the inner mitochondrial membrane. This gene encodes a complex I assembly factor. Mutations in this gene are a cause of mitochondrial complex I deficiency. [provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-96897795-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFAF4	NM_014165.4	c.7G>A	p.Ala3Thr	missense_variant	Exon 1 of 3	ENST00000316149.8	NP_054884.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFAF4	ENST00000316149.8	c.7G>A	p.Ala3Thr	missense_variant	Exon 1 of 3	1	NM_014165.4	ENSP00000358272.4
NDUFAF4	ENST00000489477.1	n.80G>A		non_coding_transcript_exon_variant	Exon 1 of 4	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461818 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727216

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

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	Benign	0.24
BayesDel_addAF	Uncertain	0.072	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.063
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.49	T
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Pathogenic	3.0	M
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.46
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.024	D
Polyphen		0.97	D
Vest4		0.43
MutPred		0.69		Gain of relative solvent accessibility (P = 0.0479);
MVP		0.86
MPC		0.40
ClinPred		0.97	D
GERP RS		4.7
Varity_R		0.23
gMVP		0.33

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: chr6-97345671;