15-41387308-CAAAAAAAAAA-CAAAAAAAAAAAA

Variant names:

• chr15-41387308-C-CAA
• rs751327964
• ENST00000560978.2:c.*134_*135dupTT

Variant summary

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

The ENST00000560978.2(NDUFAF1):​c.*134_*135dupTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0052 (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 0 ACMG points.

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_*136insTT		downstream_gene	N/A	NP_057097.2
	NDUFAF1	NM_001437486.1		c.*135_*136insTT		downstream_gene	N/A	NP_001424415.1
	NDUFAF1	NM_001437487.1		c.*135_*136insTT		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.*134_*135dupTT		3_prime_UTR	Exon 5 of 5	ENSP00000453944.2	Q9Y375
	NDUFAF1	ENST00000260361.9	TSL:1 MANE Select	c.*134_*135dupTT		downstream_gene	N/A	ENSP00000260361.4	Q9Y375
	NDUFAF1	ENST00000559127.5	TSL:1	n.*586_*587dupTT		downstream_gene	N/A	ENSP00000453027.1	H0YL22

Frequencies

GnomAD3 genomes AF: 0.000240 AC: 16 AN: 66592 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000172

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00179

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000939

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000154

Gnomad OTH AF: 0.00111

GnomAD2 exomes AF: 0.00366 AC: 152 AN: 41530 AF XY: 0.00397

Gnomad AFR exome AF: 0.00418

Gnomad AMR exome AF: 0.00456

Gnomad ASJ exome AF: 0.00445

Gnomad EAS exome AF: 0.00350

Gnomad FIN exome AF: 0.00151

Gnomad NFE exome AF: 0.00366

Gnomad OTH exome AF: 0.00151

GnomAD4 exome AF: 0.00516 AC: 2590 AN: 501844 Hom.: 0 Cov.: 0 AF XY: 0.00495 AC XY: 1316 AN XY: 265754

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

African (AFR) AF: 0.00696 AC: 87 AN: 12498

American (AMR) AF: 0.00410 AC: 77 AN: 18802

Ashkenazi Jewish (ASJ) AF: 0.00518 AC: 69 AN: 13312

East Asian (EAS) AF: 0.00571 AC: 150 AN: 26288

South Asian (SAS) AF: 0.00247 AC: 118 AN: 47740

European-Finnish (FIN) AF: 0.00437 AC: 109 AN: 24946

Middle Eastern (MID) AF: 0.00485 AC: 9 AN: 1856

European-Non Finnish (NFE) AF: 0.00554 AC: 1835 AN: 331022

Other (OTH) AF: 0.00536 AC: 136 AN: 25380

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.000240 AC: 16 AN: 66610 Hom.: 0 Cov.: 30 AF XY: 0.000322 AC XY: 10 AN XY: 31074

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

African (AFR) AF: 0.000171 AC: 3 AN: 17520

American (AMR) AF: 0.00 AC: 0 AN: 5806

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

East Asian (EAS) AF: 0.00180 AC: 4 AN: 2228

South Asian (SAS) AF: 0.00 AC: 0 AN: 2194

European-Finnish (FIN) AF: 0.000939 AC: 3 AN: 3194

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 86

European-Non Finnish (NFE) AF: 0.000154 AC: 5 AN: 32472

Other (OTH) AF: 0.00109 AC: 1 AN: 914

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000436491), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00263 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;