NM_001086521.2:c.165C>G

Variant names:

• chr17-81239648-C-G
• rs1598368033
• NM_001086521.2:c.165C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP2 PP3 PP5_Moderate

The NM_001086521.2(NDUFAF8):​c.165C>G​(p.Phe55Leu) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: NDUFAF8 NM_001086521.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 0.901
• Publications: 0 publications found

Genes affected

NDUFAF8 (HGNC:33551): (NADH:ubiquinone oxidoreductase complex assembly factor 8) Involved in mitochondrial respiratory chain complex I assembly. Located in mitochondrion. Implicated in nuclear type mitochondrial complex I deficiency 34. [provided by Alliance of Genome Resources, Apr 2022]

NDUFAF8 Gene-Disease associations (from GenCC):

• mitochondrial complex I deficiency, nuclear type 34

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics
• Leigh syndrome

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen
• mitochondrial complex I deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 1 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 0.3948 (below the threshold of 3.09). Trascript score misZ: -1.1983 (below the threshold of 3.09). GenCC associations: The gene is linked to mitochondrial complex I deficiency, nuclear type 34, mitochondrial complex I deficiency, Leigh syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.837
• PP5: Variant 17-81239648-C-G is Pathogenic according to our data. Variant chr17-81239648-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 691641.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001086521.2. 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
	NDUFAF8	NM_001086521.2	MANE Select	c.165C>G	p.Phe55Leu	missense	Exon 2 of 3	NP_001079990.1	A1L188
	NDUFAF8	NM_001353403.1		c.-259C>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 3	NP_001340332.1
	NDUFAF8	NM_001353402.1		c.165C>G	p.Phe55Leu	missense	Exon 2 of 3	NP_001340331.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFAF8	ENST00000431388.3	TSL:1 MANE Select	c.165C>G	p.Phe55Leu	missense	Exon 2 of 3	ENSP00000400184.2	A1L188
	NDUFAF8	ENST00000577158.2	TSL:1	n.153C>G		non_coding_transcript_exon	Exon 2 of 3
	NDUFAF8	ENST00000576002.1	TSL:2	c.36C>G	p.Phe12Leu	missense	Exon 1 of 2	ENSP00000461155.1	I3L4C8

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Mitochondrial complex I deficiency, nuclear type 34 (1)
1	-	-	Mitochondrial disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.044	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	T
Eigen	Benign	0.065
Eigen_PC	Benign	0.0070
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.74	T
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Benign	-0.66	T
PhyloP100		0.90
PROVEAN	Pathogenic	-6.0	D
REVEL	Benign	0.16
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.88	P
Vest4		0.76
MutPred		0.36		Gain of disorder (P = 0.1722)
MVP		0.13
MPC		0.37
ClinPred		0.93	D
GERP RS		2.5
PromoterAI		0.075	Neutral
Varity_R		0.54
gMVP		0.72
Mutation Taster		=32/68	disease causing (ClinVar)

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: rs1598368033; hg19: chr17-79213448;