rs1057519086

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5

The NM_152416.4(NDUFAF6):ā€‹c.820A>Gā€‹(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 š‘“: 0.0000014 ( 0 hom. )

Consequence

NDUFAF6
NM_152416.4 missense

Scores

6
9
4

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 2.16
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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
NDUFAF6NM_152416.4 linkuse as main transcriptc.820A>G p.Arg274Gly missense_variant 8/9 ENST00000396124.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NDUFAF6ENST00000396124.9 linkuse as main transcriptc.820A>G p.Arg274Gly missense_variant 8/92 NM_152416.4 P1Q330K2-1

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
show subpopulations
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
LINK: link

Submissions by phenotype

Mitochondrial complex 1 deficiency, nuclear type 17 Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMApr 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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1057519086; hg19: chr8-96064405; API