15-41387308-CAAAAAAAAAA-CAAAAAA

Variant names:

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

Variant summary

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

The ENST00000560978.2(NDUFAF1):​c.*132_*135delTTTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00302 in 565,702 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: 0.0034 (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 MID (0.00375) population. However there is too low homozygotes in high coverage region: (expected more than 1, 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.*132_*135delTTTT		downstream_gene	N/A	NP_057097.2
	NDUFAF1	NM_001437486.1		c.*132_*135delTTTT		downstream_gene	N/A	NP_001424415.1
	NDUFAF1	NM_001437487.1		c.*132_*135delTTTT		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_*135delTTTT		3_prime_UTR	Exon 5 of 5	ENSP00000453944.2	Q9Y375
	NDUFAF1	ENST00000260361.9	TSL:1 MANE Select	c.*132_*135delTTTT		downstream_gene	N/A	ENSP00000260361.4	Q9Y375
	NDUFAF1	ENST00000559127.5	TSL:1	n.*584_*587delTTTT		downstream_gene	N/A	ENSP00000453027.1	H0YL22

Frequencies

GnomAD3 genomes AF: 0.0000599 AC: 4 AN: 66726 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000344

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000627

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00371 AC: 154 AN: 41530 AF XY: 0.00434

Gnomad AFR exome AF: 0.00278

Gnomad AMR exome AF: 0.00403

Gnomad ASJ exome AF: 0.00636

Gnomad EAS exome AF: 0.00331

Gnomad FIN exome AF: 0.00227

Gnomad NFE exome AF: 0.00353

Gnomad OTH exome AF: 0.00377

GnomAD4 exome AF: 0.00342 AC: 1705 AN: 498976 Hom.: 0 AF XY: 0.00342 AC XY: 903 AN XY: 264038

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

African (AFR) AF: 0.00393 AC: 49 AN: 12468

American (AMR) AF: 0.00274 AC: 51 AN: 18642

Ashkenazi Jewish (ASJ) AF: 0.00393 AC: 52 AN: 13240

East Asian (EAS) AF: 0.00348 AC: 91 AN: 26114

South Asian (SAS) AF: 0.00275 AC: 130 AN: 47300

European-Finnish (FIN) AF: 0.00331 AC: 82 AN: 24768

Middle Eastern (MID) AF: 0.00651 AC: 12 AN: 1844

European-Non Finnish (NFE) AF: 0.00353 AC: 1162 AN: 329374

Other (OTH) AF: 0.00301 AC: 76 AN: 25226

⚠️ 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: 0.0000599 AC: 4 AN: 66726 Hom.: 0 Cov.: 30 AF XY: 0.0000643 AC XY: 2 AN XY: 31098

⚠️ 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: 17522

American (AMR) AF: 0.000344 AC: 2 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: 0.000627 AC: 2 AN: 3190

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 32562

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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000507 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;