15-41387308-C-CA

Variant names:

• chr15-41387308-C-CA
• rs751327964
• ENST00000560978.2:c.*135dupT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The ENST00000560978.2(NDUFAF1):​c.*135dupT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0779 in 566,786 control chromosomes in the GnomAD database, including 22 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.020 (22 hom., cov: 30)
  • Exomes 𝑓: 0.086 (0 hom.)
• Consequence: NDUFAF1 ENST00000560978.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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: Benign. The variant received -10 ACMG points.

• BP6: Variant 15-41387308-C-CA is Benign according to our data. Variant chr15-41387308-C-CA is described in ClinVar as Benign. ClinVar VariationId is 1228185.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0525 is higher than 0.05.

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

Frequencies

GnomAD3 genomes AF: 0.0204 AC: 1357 AN: 66408 Hom.: 21 Cov.: 30

Gnomad AFR AF: 0.0554

Gnomad AMI AF: 0.00253

Gnomad AMR AF: 0.0117

Gnomad ASJ AF: 0.00167

Gnomad EAS AF: 0.0327

Gnomad SAS AF: 0.0104

Gnomad FIN AF: 0.00595

Gnomad MID AF: 0.106

Gnomad NFE AF: 0.00525

Gnomad OTH AF: 0.0268

GnomAD2 exomes AF: 0.0671 AC: 2785 AN: 41530 AF XY: 0.0651

Gnomad AFR exome AF: 0.104

Gnomad AMR exome AF: 0.0672

Gnomad ASJ exome AF: 0.0553

Gnomad EAS exome AF: 0.0734

Gnomad FIN exome AF: 0.0242

Gnomad NFE exome AF: 0.0644

Gnomad OTH exome AF: 0.0724

GnomAD4 exome AF: 0.0855 AC: 42787 AN: 500360 Hom.: 0 Cov.: 0 AF XY: 0.0853 AC XY: 22583 AN XY: 264772

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

African (AFR) AF: 0.108 AC: 1340 AN: 12458

American (AMR) AF: 0.0714 AC: 1335 AN: 18698

Ashkenazi Jewish (ASJ) AF: 0.0812 AC: 1079 AN: 13296

East Asian (EAS) AF: 0.0944 AC: 2475 AN: 26206

South Asian (SAS) AF: 0.0627 AC: 2961 AN: 47260

European-Finnish (FIN) AF: 0.0750 AC: 1868 AN: 24912

Middle Eastern (MID) AF: 0.0958 AC: 177 AN: 1848

European-Non Finnish (NFE) AF: 0.0888 AC: 29337 AN: 330374

Other (OTH) AF: 0.0875 AC: 2215 AN: 25308

⚠️ 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: 0.0205 AC: 1359 AN: 66426 Hom.: 22 Cov.: 30 AF XY: 0.0210 AC XY: 650 AN XY: 30974

African (AFR) AF: 0.0553 AC: 968 AN: 17490

American (AMR) AF: 0.0117 AC: 68 AN: 5796

Ashkenazi Jewish (ASJ) AF: 0.00167 AC: 3 AN: 1798

East Asian (EAS) AF: 0.0329 AC: 73 AN: 2220

South Asian (SAS) AF: 0.0105 AC: 23 AN: 2192

European-Finnish (FIN) AF: 0.00595 AC: 19 AN: 3192

Middle Eastern (MID) AF: 0.102 AC: 9 AN: 88

European-Non Finnish (NFE) AF: 0.00523 AC: 169 AN: 32344

Other (OTH) AF: 0.0286 AC: 26 AN: 910

Alfa AF: 0.00694 Hom.: 1

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.23
Mutation Taster		=100/0	polymorphism

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;