15-41387308-CAAAAAAAAAA-CAAAAAAAA

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP6_Moderate

The ENST00000560978.2(NDUFAF1):​c.*134_*135delTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.043 in 539,804 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00079 (0 hom., cov: 30)
  • Exomes 𝑓: 0.049 (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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Variant has high frequency in the AMR (0.0513) population. However there is too low homozygotes in high coverage region: (expected more than 249, got 0).
• BP6: Variant 15-41387308-CAA-C is Benign according to our data. Variant chr15-41387308-CAA-C is described in ClinVar as Benign. ClinVar VariationId is 1238975.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Frequencies

GnomAD3 genomes AF: 0.000795 AC: 53 AN: 66678 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00183

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000860

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00134

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00253

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000154

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0696 AC: 2891 AN: 41530 AF XY: 0.0702

Gnomad AFR exome AF: 0.0651

Gnomad AMR exome AF: 0.0821

Gnomad ASJ exome AF: 0.0566

Gnomad EAS exome AF: 0.0806

Gnomad FIN exome AF: 0.0249

Gnomad NFE exome AF: 0.0644

Gnomad OTH exome AF: 0.0777

GnomAD4 exome AF: 0.0490 AC: 23179 AN: 473108 Hom.: 0 AF XY: 0.0481 AC XY: 12024 AN XY: 250046

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

African (AFR) AF: 0.0442 AC: 518 AN: 11728

American (AMR) AF: 0.0542 AC: 931 AN: 17178

Ashkenazi Jewish (ASJ) AF: 0.0507 AC: 640 AN: 12620

East Asian (EAS) AF: 0.0514 AC: 1267 AN: 24656

South Asian (SAS) AF: 0.0484 AC: 2100 AN: 43366

European-Finnish (FIN) AF: 0.0537 AC: 1270 AN: 23646

Middle Eastern (MID) AF: 0.0485 AC: 85 AN: 1754

European-Non Finnish (NFE) AF: 0.0481 AC: 15116 AN: 314174

Other (OTH) AF: 0.0522 AC: 1252 AN: 23986

⚠️ 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: 0.000795 AC: 53 AN: 66696 Hom.: 0 Cov.: 30 AF XY: 0.000739 AC XY: 23 AN XY: 31104

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

African (AFR) AF: 0.00182 AC: 32 AN: 17550

American (AMR) AF: 0.000860 AC: 5 AN: 5816

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

East Asian (EAS) AF: 0.00135 AC: 3 AN: 2228

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

European-Finnish (FIN) AF: 0.00253 AC: 8 AN: 3164

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

European-Non Finnish (NFE) AF: 0.000154 AC: 5 AN: 32540

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 = 0.000000000000390687), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00117 Hom.: 1

ClinVar

ClinVar submissions as Germline

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

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;