5-60945335-A-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_174889.5(NDUFAF2):c.80A>T(p.Gln27Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000867 in 1,614,168 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: NDUFAF2 NM_174889.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.263

Genes affected

NDUFAF2 (HGNC:28086): (NADH:ubiquinone oxidoreductase complex assembly factor 2) NADH:ubiquinone oxidoreductase (complex I) catalyzes the transfer of electrons from NADH to ubiquinone (coenzyme Q) in the first step of the mitochondrial respiratory chain, resulting in the translocation of protons across the inner mitochondrial membrane. This gene encodes a complex I assembly factor. Mutations in this gene cause progressive encephalopathy resulting from mitochondrial complex I deficiency. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07839787).
• BP6: Variant 5-60945335-A-T is Benign according to our data. Variant chr5-60945335-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 214739.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NDUFAF2	NM_174889.5	c.80A>T	p.Gln27Leu	missense_variant	1/4	ENST00000296597.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NDUFAF2	ENST00000296597.10	c.80A>T	p.Gln27Leu	missense_variant	1/4	1	NM_174889.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152178 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251308 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135854

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461872 Hom.: 0 Cov.: 37 AF XY: 0.00000688 AC XY: 5 AN XY: 727234

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152296 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74460

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000264

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 05, 2022

The c.80A>T (p.Q27L) alteration is located in exon 1 (coding exon 1) of the NDUFAF2 gene. This alteration results from a A to T substitution at nucleotide position 80, causing the glutamine (Q) at amino acid position 27 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 01, 2013

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.089	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	15
Dann	Benign	0.97
DEOGEN2	Benign	0.017	T;.
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.61	T;T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.078	T;T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-1.3	N;D
REVEL	Benign	0.022
Sift	Benign	0.33	T;D
Sift4G	Benign	0.62	T;D
Polyphen		0.0010	B;.
Vest4		0.15
MutPred		0.30		Loss of disorder (P = 0.0429);Loss of disorder (P = 0.0429);
MVP		0.50
MPC		0.073
ClinPred		0.042	T
GERP RS		1.1
Varity_R		0.14
gMVP		0.39

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: rs753215899; hg19: chr5-60241162;