15-41387308-CAAAAAAAAAA-CAAAAAAA

Variant names:

• chr15-41387308-CAAA-C
• rs751327964
• ENST00000560978.2:c.*133_*135delTTT

Variant summary

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

The ENST00000560978.2(NDUFAF1):​c.*133_*135delTTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00998 in 557,156 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 0.000060 (0 hom., cov: 30)
  • Exomes 𝑓: 0.011 (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: Variant has high frequency in the EAS (0.0118) population. However there is too low homozygotes in high coverage region: (expected more than 13, got 0).

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.*133_*135delTTT		downstream_gene	N/A	NP_057097.2
	NDUFAF1	NM_001437486.1		c.*133_*135delTTT		downstream_gene	N/A	NP_001424415.1
	NDUFAF1	NM_001437487.1		c.*133_*135delTTT		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.*133_*135delTTT		3_prime_UTR	Exon 5 of 5	ENSP00000453944.2	Q9Y375
	NDUFAF1	ENST00000260361.9	TSL:1 MANE Select	c.*133_*135delTTT		downstream_gene	N/A	ENSP00000260361.4	Q9Y375
	NDUFAF1	ENST00000559127.5	TSL:1	n.*585_*587delTTT		downstream_gene	N/A	ENSP00000453027.1	H0YL22

Frequencies

GnomAD3 genomes AF: 0.0000600 AC: 4 AN: 66706 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: 0.000629

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000614

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0163 AC: 677 AN: 41530 AF XY: 0.0165

Gnomad AFR exome AF: 0.0134

Gnomad AMR exome AF: 0.0191

Gnomad ASJ exome AF: 0.0248

Gnomad EAS exome AF: 0.0154

Gnomad FIN exome AF: 0.0121

Gnomad NFE exome AF: 0.0143

Gnomad OTH exome AF: 0.0181

GnomAD4 exome AF: 0.0113 AC: 5555 AN: 490450 Hom.: 0 AF XY: 0.0112 AC XY: 2894 AN XY: 259520

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

African (AFR) AF: 0.00959 AC: 118 AN: 12302

American (AMR) AF: 0.0101 AC: 183 AN: 18204

Ashkenazi Jewish (ASJ) AF: 0.0153 AC: 199 AN: 13024

East Asian (EAS) AF: 0.0129 AC: 331 AN: 25640

South Asian (SAS) AF: 0.0103 AC: 471 AN: 45858

European-Finnish (FIN) AF: 0.0125 AC: 304 AN: 24370

Middle Eastern (MID) AF: 0.0115 AC: 21 AN: 1822

European-Non Finnish (NFE) AF: 0.0112 AC: 3645 AN: 324434

Other (OTH) AF: 0.0114 AC: 283 AN: 24796

⚠️ 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: 0.0000600 AC: 4 AN: 66706 Hom.: 0 Cov.: 30 AF XY: 0.0000322 AC XY: 1 AN XY: 31088

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

African (AFR) AF: 0.00 AC: 0 AN: 17520

American (AMR) AF: 0.00 AC: 0 AN: 5808

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1802

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

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

European-Finnish (FIN) AF: 0.000629 AC: 2 AN: 3180

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

European-Non Finnish (NFE) AF: 0.0000614 AC: 2 AN: 32556

Other (OTH) AF: 0.00 AC: 0 AN: 898

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000000482131), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000355 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;