17-81239391-C-G

Variant names:

• chr17-81239391-C-G
• rs377540343
• NM_001086521.2:c.28C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001086521.2(NDUFAF8):​c.28C>G​(p.Arg10Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000804 in 1,367,958 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. R10C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000074 (0 hom.)
• Consequence: NDUFAF8 NM_001086521.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.16
• Publications: 1 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: Uncertain_significance. The variant received 3 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, Leigh syndrome, mitochondrial complex I deficiency.

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.28C>G	p.Arg10Gly	missense	Exon 1 of 3	NP_001079990.1	A1L188
	NDUFAF8	NM_001353402.1		c.28C>G	p.Arg10Gly	missense	Exon 1 of 3	NP_001340331.1
	NDUFAF8	NM_001353403.1		c.-396C>G		5_prime_UTR	Exon 1 of 3	NP_001340332.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFAF8	ENST00000431388.3	TSL:1 MANE Select	c.28C>G	p.Arg10Gly	missense	Exon 1 of 3	ENSP00000400184.2	A1L188
	NDUFAF8	ENST00000577158.2	TSL:1	n.87C>G		non_coding_transcript_exon	Exon 1 of 3
	NDUFAF8	ENST00000573090.1	TSL:3	n.81C>G		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152216 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000740 AC: 9 AN: 1215742 Hom.: 0 Cov.: 31 AF XY: 0.00000171 AC XY: 1 AN XY: 586084

African (AFR) AF: 0.00 AC: 0 AN: 23466

American (AMR) AF: 0.00 AC: 0 AN: 9732

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16666

East Asian (EAS) AF: 0.0000366 AC: 1 AN: 27286

South Asian (SAS) AF: 0.00 AC: 0 AN: 51096

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42504

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3358

European-Non Finnish (NFE) AF: 0.00000806 AC: 8 AN: 991952

Other (OTH) AF: 0.00 AC: 0 AN: 49682

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152216 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74364

African (AFR) AF: 0.00 AC: 0 AN: 41458

American (AMR) AF: 0.000131 AC: 2 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	27
DANN	Benign	0.97
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.088
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.66	T
M_CAP	Pathogenic	0.30	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Benign	-0.74	T
PhyloP100		4.2
PROVEAN	Uncertain	-3.8	D
REVEL	Benign	0.13
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.017	D
Polyphen		0.011	B
Vest4		0.78
MutPred		0.29		Loss of methylation at R10 (P = 0.0152)
MVP		0.11
MPC		0.93
ClinPred		0.82	D
GERP RS		3.8
PromoterAI		0.086	Neutral
Varity_R		0.39
gMVP		0.49
Mutation Taster		=97/3	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: rs377540343; hg19: chr17-79213191;