chr5-60949318-A-G

Variant names:

• chr5-60949318-A-G
• rs158916
• NM_174889.5:c.127+3936A>G

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+3936A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.148 in 152,162 control chromosomes in the GnomAD database, including 2,141 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 0.15 (2141 hom., cov: 32)
• Consequence: NDUFAF2 NM_174889.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.875
• Publications: 8 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=-0.66).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.267 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFAF2	NM_174889.5	c.127+3936A>G		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+3936A>G		intron_variant	Intron 1 of 3	1	NM_174889.5	ENSP00000296597.5

Frequencies

GnomAD3 genomes AF: 0.148 AC: 22565 AN: 152044 Hom.: 2133 Cov.: 32

Gnomad AFR AF: 0.0440

Gnomad AMI AF: 0.213

Gnomad AMR AF: 0.230

Gnomad ASJ AF: 0.150

Gnomad EAS AF: 0.140

Gnomad SAS AF: 0.280

Gnomad FIN AF: 0.200

Gnomad MID AF: 0.213

Gnomad NFE AF: 0.176

Gnomad OTH AF: 0.146

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

GnomAD4 genome AF: 0.148 AC: 22590 AN: 152162 Hom.: 2141 Cov.: 32 AF XY: 0.153 AC XY: 11389 AN XY: 74380

African (AFR) AF: 0.0442 AC: 1835 AN: 41548

American (AMR) AF: 0.230 AC: 3521 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.150 AC: 521 AN: 3470

East Asian (EAS) AF: 0.140 AC: 723 AN: 5166

South Asian (SAS) AF: 0.279 AC: 1347 AN: 4826

European-Finnish (FIN) AF: 0.200 AC: 2118 AN: 10564

Middle Eastern (MID) AF: 0.199 AC: 58 AN: 292

European-Non Finnish (NFE) AF: 0.176 AC: 11952 AN: 67988

Other (OTH) AF: 0.152 AC: 321 AN: 2106

Alfa AF: 0.163 Hom.: 347

Bravo AF: 0.142

Asia WGS AF: 0.214 AC: 745 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	14
DANN	Benign	0.78
PhyloP100		0.88
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: rs158916; hg19: chr5-60245145;