6-96891212-C-G

Variant names:

• chr6-96891212-C-G
• rs11402
• NM_014165.4:c.420G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_014165.4(NDUFAF4):​c.420G>C​(p.Gln140His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign 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. Q140R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: NDUFAF4 NM_014165.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0870
• Publications: 25 publications found

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]

NDUFAF4 Gene-Disease associations (from GenCC):

• mitochondrial complex I deficiency, nuclear type 15

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• mitochondrial complex I deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Leigh syndrome

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3361796).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFAF4	NM_014165.4	c.420G>C	p.Gln140His	missense_variant	Exon 3 of 3	ENST00000316149.8	NP_054884.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFAF4	ENST00000316149.8	c.420G>C	p.Gln140His	missense_variant	Exon 3 of 3	1	NM_014165.4	ENSP00000358272.4
NDUFAF4	ENST00000478382.1	n.355G>C		non_coding_transcript_exon_variant	Exon 2 of 2	2
NDUFAF4	ENST00000489477.1	n.563G>C		non_coding_transcript_exon_variant	Exon 4 of 4	3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 46

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.014	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.58	D
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.85	T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.34	T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		-0.087
PrimateAI	Benign	0.25	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.47
Sift	Uncertain	0.018	D
Sift4G	Benign	0.063	T
Polyphen		0.87	P
Vest4		0.16
MutPred		0.45		Loss of helix (P = 0.1299);
MVP		0.84
MPC		0.80
ClinPred		0.96	D
GERP RS		1.2
Varity_R		0.090
gMVP		0.37
Mutation Taster		=80/20	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: rs11402; hg19: chr6-97339088;