15-41387487-G-T

Variant names:

• chr15-41387487-G-T
• rs12900702
• NM_016013.4:c.941C>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_016013.4(NDUFAF1):​c.941C>A​(p.Ala314Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,152 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A314G) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NDUFAF1 NM_016013.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.05
• Publications: 20 publications found

Genes affected

NDUFAF1 (HGNC:18828): (NADH:ubiquinone oxidoreductase complex assembly factor 1) This gene encodes a complex I assembly factor protein. Complex I (NADH-ubiquinone oxidoreductase) 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. The encoded protein is required for assembly of complex I, and mutations in this gene are a cause of mitochondrial complex I deficiency. Alternatively spliced transcript variants have been observed for this gene, and a pseudogene of this gene is located on the long arm of chromosome 19. [provided by RefSeq, Dec 2011]

NDUFAF1 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen
• mitochondrial complex I deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mitochondrial complex I deficiency, nuclear type 11

  Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.869

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016013.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFAF1	NM_016013.4	MANE Select	c.941C>A	p.Ala314Asp	missense	Exon 5 of 5	NP_057097.2
	NDUFAF1	NM_001437486.1		c.941C>A	p.Ala314Asp	missense	Exon 5 of 5	NP_001424415.1
	NDUFAF1	NM_001437487.1		c.941C>A	p.Ala314Asp	missense	Exon 5 of 5	NP_001424416.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFAF1	ENST00000260361.9	TSL:1 MANE Select	c.941C>A	p.Ala314Asp	missense	Exon 5 of 5	ENSP00000260361.4	Q9Y375
	NDUFAF1	ENST00000853315.1		c.1025C>A	p.Ala342Asp	missense	Exon 5 of 5	ENSP00000523374.1
	NDUFAF1	ENST00000560978.2	TSL:3	c.941C>A	p.Ala314Asp	missense	Exon 5 of 5	ENSP00000453944.2	Q9Y375

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251390 AF XY: 0.00000736

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461152 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726958

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111366

Other (OTH) AF: 0.00 AC: 0 AN: 60366

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.041	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Benign	-0.45	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		9.1
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Uncertain	0.51
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.99	D
Vest4		0.92
MutPred		0.28		Gain of disorder (P = 0.1073)
MVP		0.92
MPC		0.51
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.84
gMVP		0.88

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: rs12900702; hg19: chr15-41679685;