rs1057519086

Positions:

• chr8-95052177-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_152416.4(NDUFAF6):​c.820A>G​(p.Arg274Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,802 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NDUFAF6 NM_152416.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.16

Genes affected

NDUFAF6 (HGNC:28625): (NADH:ubiquinone oxidoreductase complex assembly factor 6) This gene encodes a protein that localizes to mitochondria and contains a predicted phytoene synthase domain. The encoded protein plays an important role in the assembly of complex I (NADH-ubiquinone oxidoreductase) of the mitochondrial respiratory chain through regulation of subunit ND1 biogenesis. Mutations in this gene are associated with complex I enzymatic deficiency. [provided by RefSeq, Nov 2011]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_152416.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.952
• PP5: Variant 8-95052177-A-G is Pathogenic according to our data. Variant chr8-95052177-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 372259.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NDUFAF6	NM_152416.4	c.820A>G	p.Arg274Gly	missense_variant	8/9	ENST00000396124.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NDUFAF6	ENST00000396124.9	c.820A>G	p.Arg274Gly	missense_variant	8/9	2	NM_152416.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461802 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727202

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Mitochondrial complex 1 deficiency, nuclear type 17 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T;T;D
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.92	.;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Uncertain	-0.029	T
MutationAssessor	Pathogenic	3.4	.;.;M
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-5.3	D;D;D
REVEL	Pathogenic	0.77
Sift	Benign	0.078	T;T;D
Sift4G	Uncertain	0.0070	D;D;D
Polyphen		0.99	.;.;D
Vest4		0.91
MutPred		0.80		.;.;Loss of methylation at R274 (P = 0.0148);
MVP		0.74
MPC		0.66
ClinPred		0.97	D
GERP RS		4.5
Varity_R		0.73
gMVP		0.85

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: rs1057519086; hg19: chr8-96064405;