15-41387308-CAAAAAAAAAA-CAAAAAAAAAAAAAAA

Variant names:

• chr15-41387308-C-CAAAAA
• rs751327964
• ENST00000560978.2:c.*131_*135dupTTTTT

Variant summary

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

The ENST00000560978.2(NDUFAF1):​c.*131_*135dupTTTTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000015 in 66,756 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: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• 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_*136insTTTTT		downstream_gene	N/A	NP_057097.2
	NDUFAF1	NM_001437486.1		c.*135_*136insTTTTT		downstream_gene	N/A	NP_001424415.1
	NDUFAF1	NM_001437487.1		c.*135_*136insTTTTT		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.*131_*135dupTTTTT		3_prime_UTR	Exon 5 of 5	ENSP00000453944.2	Q9Y375
	NDUFAF1	ENST00000260361.9	TSL:1 MANE Select	c.*131_*135dupTTTTT		downstream_gene	N/A	ENSP00000260361.4	Q9Y375
	NDUFAF1	ENST00000559127.5	TSL:1	n.*583_*587dupTTTTT		downstream_gene	N/A	ENSP00000453027.1	H0YL22

Frequencies

GnomAD3 genomes AF: 0.0000300 AC: 2 AN: 66738 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000571

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 Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 505504 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 267648

African (AFR) AF: 0.00 AC: 0 AN: 12628

American (AMR) AF: 0.00 AC: 0 AN: 18940

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13430

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 48052

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25102

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1876

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 333386

Other (OTH) AF: 0.00 AC: 0 AN: 25584

GnomAD4 genome AF: 0.0000150 AC: 1 AN: 66756 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 31132

⚠️ 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: 17558

American (AMR) AF: 0.00 AC: 0 AN: 5816

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 2228

South Asian (SAS) AF: 0.00 AC: 0 AN: 2200

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 88

European-Non Finnish (NFE) AF: 0.0000307 AC: 1 AN: 32560

Other (OTH) AF: 0.00 AC: 0 AN: 914

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00233887), which strongly suggests a high chance of mosaicism in these individuals.

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;