chr5-61001597-G-A

Variant names:

• chr5-61001597-G-A
• rs162244
• NM_174889.5:c.127+56215G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_174889.5(NDUFAF2):​c.127+56215G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.636 in 151,966 control chromosomes in the GnomAD database, including 31,198 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.64 (31198 hom., cov: 33)
• Consequence: NDUFAF2 NM_174889.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.509
• Publications: 9 publications found

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]

NDUFAF2 Gene-Disease associations (from GenCC):

• Leigh syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, G2P
• mitochondrial complex I deficiency, nuclear type 10

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Leigh syndrome with leukodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mitochondrial complex I deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.922 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFAF2	NM_174889.5	c.127+56215G>A		intron_variant	Intron 1 of 3	ENST00000296597.10	NP_777549.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFAF2	ENST00000296597.10	c.127+56215G>A		intron_variant	Intron 1 of 3	1	NM_174889.5	ENSP00000296597.5

Frequencies

GnomAD3 genomes AF: 0.636 AC: 96648 AN: 151848 Hom.: 31170 Cov.: 33

Gnomad AFR AF: 0.627

Gnomad AMI AF: 0.825

Gnomad AMR AF: 0.684

Gnomad ASJ AF: 0.570

Gnomad EAS AF: 0.944

Gnomad SAS AF: 0.672

Gnomad FIN AF: 0.639

Gnomad MID AF: 0.611

Gnomad NFE AF: 0.606

Gnomad OTH AF: 0.620

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.636 AC: 96720 AN: 151966 Hom.: 31198 Cov.: 33 AF XY: 0.640 AC XY: 47533 AN XY: 74276

African (AFR) AF: 0.627 AC: 25989 AN: 41424

American (AMR) AF: 0.684 AC: 10440 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.570 AC: 1980 AN: 3472

East Asian (EAS) AF: 0.944 AC: 4883 AN: 5172

South Asian (SAS) AF: 0.672 AC: 3234 AN: 4814

European-Finnish (FIN) AF: 0.639 AC: 6755 AN: 10566

Middle Eastern (MID) AF: 0.602 AC: 177 AN: 294

European-Non Finnish (NFE) AF: 0.606 AC: 41199 AN: 67940

Other (OTH) AF: 0.624 AC: 1314 AN: 2106

Alfa AF: 0.603 Hom.: 3444

Bravo AF: 0.641

Asia WGS AF: 0.818 AC: 2839 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.9
DANN	Benign	0.70
PhyloP100		0.51
Mutation Taster		=100/0	polymorphism (auto)

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: rs162244; hg19: chr5-60297424; COSMIC: COSV56941014;