17-81239648-C-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3 PP5_Moderate

The NM_001353403.1(NDUFAF8):​c.-259C>G variant causes a 5 prime UTR premature start codon gain 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_001353403.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 0.901

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 id is 691641.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-81239648-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFAF8	NM_001086521.2	c.165C>G	p.Phe55Leu	missense_variant	Exon 2 of 3	ENST00000431388.3	NP_001079990.1
NDUFAF8	NM_001353403.1	c.-259C>G		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 3		NP_001340332.1
NDUFAF8	NM_001353402.1	c.165C>G	p.Phe55Leu	missense_variant	Exon 2 of 3		NP_001340331.1
NDUFAF8	NM_001353403.1	c.-259C>G		5_prime_UTR_variant	Exon 2 of 3		NP_001340332.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFAF8	ENST00000431388.3	c.165C>G	p.Phe55Leu	missense_variant	Exon 2 of 3	1	NM_001086521.2	ENSP00000400184.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 34

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Mitochondrial disease Pathogenic:1

Oct 09, 2019

Wellcome Centre for Mitochondrial Research, Newcastle University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mitochondrial complex 1 deficiency, nuclear type 34 Pathogenic:1

Feb 19, 2020

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

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
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
Varity_R		0.54
gMVP		0.72

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

LitVar

Other links and lift over

dbSNP: rs1598368033; hg19: chr17-79213448;