chr20-13785069-A-C

Variant names:

• chr20-13785069-A-C
• rs758736270
• NM_024120.5:c.1A>C

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_001352403.2(NDUFAF5):​c.-367A>C variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000549 in 1,458,394 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: NDUFAF5 NM_001352403.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 1.41
• Publications: 1 publications found

Genes affected

NDUFAF5 (HGNC:15899): (NADH:ubiquinone oxidoreductase complex assembly factor 5) The NADH-ubiquinone oxidoreductase complex (complex I) of the mitochondrial respiratory chain catalyzes the transfer of electrons from NADH to ubiquinone, and consists of at least 43 subunits. The complex is located in the inner mitochondrial membrane. This gene encodes a mitochondrial protein that is associated with the matrix face of the mitochondrial inner membrane and is required for complex I assembly. A mutation in this gene results in mitochondrial complex I deficiency. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2009]

ESF1 (HGNC:15898): (ESF1 nucleolar pre-rRNA processing protein homolog) Enables RNA binding activity. Predicted to be involved in rRNA processing. Located in extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.937
• PP5: Variant 20-13785069-A-C is Pathogenic according to our data. Variant chr20-13785069-A-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 2703746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001352403.2. 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
	NDUFAF5	NM_024120.5	MANE Select	c.1A>C	p.Met1?	initiator_codon	Exon 1 of 11	NP_077025.2
	NDUFAF5	NM_001352403.2		c.-367A>C		5_prime_UTR_premature_start_codon_gain	Exon 1 of 10	NP_001339332.1
	NDUFAF5	NM_001352406.2		c.-581A>C		5_prime_UTR_premature_start_codon_gain	Exon 1 of 11	NP_001339335.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFAF5	ENST00000378106.10	TSL:1 MANE Select	c.1A>C	p.Met1?	initiator_codon	Exon 1 of 11	ENSP00000367346.5	Q5TEU4-1
	NDUFAF5	ENST00000463598.1	TSL:1	c.1A>C	p.Met1?	initiator_codon	Exon 1 of 10	ENSP00000420497.1	Q5TEU4-2
	NDUFAF5	ENST00000874783.1		c.1A>C	p.Met1?	initiator_codon	Exon 1 of 12	ENSP00000544842.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000164 AC: 4 AN: 243694 AF XY: 0.00000752

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000117

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000549 AC: 8 AN: 1458394 Hom.: 0 Cov.: 31 AF XY: 0.00000551 AC XY: 4 AN XY: 725460

African (AFR) AF: 0.00 AC: 0 AN: 33416

American (AMR) AF: 0.000157 AC: 7 AN: 44614

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26066

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86018

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52142

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4912

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111390

Other (OTH) AF: 0.00 AC: 0 AN: 60156

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Mitochondrial complex I deficiency, nuclear type 16 (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Pathogenic	0.28
CADD	Benign	16
DANN	Benign	0.87
DEOGEN2	Benign	0.021	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Benign	-0.62	T
PhyloP100		1.4
PROVEAN	Benign	-0.38	N
REVEL	Uncertain	0.45
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.90	T
Polyphen		0.031	B
Vest4		0.52
MutPred		0.97		Gain of helix (P = 0.0199)
MVP		0.73
ClinPred		0.86	D
GERP RS		4.6
PromoterAI		0.32	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.96
gMVP		0.55
Mutation Taster		=57/143	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs758736270; hg19: chr20-13765715;