15-41387308-CAAAAAAAAAA-CAAAAAAAAAAAAAA

Variant names:

• chr15-41387308-C-CAAAA
• rs751327964
• ENST00000560978.2:c.*132_*135dupTTTT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The ENST00000560978.2(NDUFAF1):​c.*132_*135dupTTTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000315 in 572,212 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000015 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: NDUFAF1 ENST00000560978.2 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.231
• Publications: 1 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000560978.2. 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.*135_*136insTTTT		downstream_gene	N/A	NP_057097.2
	NDUFAF1	NM_001437486.1		c.*135_*136insTTTT		downstream_gene	N/A	NP_001424415.1
	NDUFAF1	NM_001437487.1		c.*135_*136insTTTT		downstream_gene	N/A	NP_001424416.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFAF1	ENST00000560978.2	TSL:3	c.*132_*135dupTTTT		3_prime_UTR	Exon 5 of 5	ENSP00000453944.2	Q9Y375
	NDUFAF1	ENST00000260361.9	TSL:1 MANE Select	c.*132_*135dupTTTT		downstream_gene	N/A	ENSP00000260361.4	Q9Y375
	NDUFAF1	ENST00000559127.5	TSL:1	n.*584_*587dupTTTT		downstream_gene	N/A	ENSP00000453027.1	H0YL22

Frequencies

GnomAD3 genomes AF: 0.0000150 AC: 1 AN: 66740 Hom.: 0 Cov.: 30

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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000307

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000336 AC: 17 AN: 505472 Hom.: 0 Cov.: 0 AF XY: 0.0000262 AC XY: 7 AN XY: 267642

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000792 AC: 1 AN: 12626

American (AMR) AF: 0.000106 AC: 2 AN: 18940

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13428

East Asian (EAS) AF: 0.00 AC: 0 AN: 26506

South Asian (SAS) AF: 0.0000208 AC: 1 AN: 48052

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25098

Middle Eastern (MID) AF: 0.000533 AC: 1 AN: 1876

European-Non Finnish (NFE) AF: 0.0000360 AC: 12 AN: 333368

Other (OTH) AF: 0.00 AC: 0 AN: 25578

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000150 AC: 1 AN: 66740 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 31104

African (AFR) AF: 0.00 AC: 0 AN: 17522

American (AMR) AF: 0.00 AC: 0 AN: 5812

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1800

East Asian (EAS) AF: 0.00 AC: 0 AN: 2240

South Asian (SAS) AF: 0.00 AC: 0 AN: 2212

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3194

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 94

European-Non Finnish (NFE) AF: 0.0000307 AC: 1 AN: 32570

Other (OTH) AF: 0.00 AC: 0 AN: 900

Alfa AF: 0.00 Hom.: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.23

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs751327964; hg19: chr15-41679506;