15-41387308-CAAAAAAAAAA-CAAAAAAAAAAAAA

Variant names:

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

Variant summary

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

The ENST00000560978.2(NDUFAF1):​c.*133_*135dupTTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00032 in 571,728 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: 0.00036 (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 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_*136insTTT		downstream_gene	N/A	NP_057097.2
	NDUFAF1	NM_001437486.1		c.*135_*136insTTT		downstream_gene	N/A	NP_001424415.1
	NDUFAF1	NM_001437487.1		c.*135_*136insTTT		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_*135dupTTT		3_prime_UTR	Exon 5 of 5	ENSP00000453944.2	Q9Y375
	NDUFAF1	ENST00000260361.9	TSL:1 MANE Select	c.*133_*135dupTTT		downstream_gene	N/A	ENSP00000260361.4	Q9Y375
	NDUFAF1	ENST00000559127.5	TSL:1	n.*585_*587dupTTT		downstream_gene	N/A	ENSP00000453027.1	H0YL22

Frequencies

GnomAD3 genomes AF: 0.0000150 AC: 1 AN: 66732 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: 0.000313

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000360 AC: 182 AN: 504996 Hom.: 0 Cov.: 0 AF XY: 0.000396 AC XY: 106 AN XY: 267360

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

African (AFR) AF: 0.000238 AC: 3 AN: 12618

American (AMR) AF: 0.000423 AC: 8 AN: 18920

Ashkenazi Jewish (ASJ) AF: 0.000298 AC: 4 AN: 13420

East Asian (EAS) AF: 0.000264 AC: 7 AN: 26470

South Asian (SAS) AF: 0.000271 AC: 13 AN: 48014

European-Finnish (FIN) AF: 0.000120 AC: 3 AN: 25084

Middle Eastern (MID) AF: 0.000535 AC: 1 AN: 1870

European-Non Finnish (NFE) AF: 0.000393 AC: 131 AN: 333050

Other (OTH) AF: 0.000470 AC: 12 AN: 25550

⚠️ 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: 66732 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 31100

African (AFR) AF: 0.00 AC: 0 AN: 17518

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

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: 0.000313 AC: 1 AN: 3194

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 32564

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

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;