rs762093523

Variant names:

• chr8-95045545-GA-G
• rs762093523
• NM_152416.4:c.485delA

Your query was ambiguous. Multiple possible variants found:

• chr8-95045545-GA-G
• chr8-95045545-GA-GAA

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_152416.4(NDUFAF6):​c.485delA​(p.Asn162IlefsTer27) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000559 in 1,610,390 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: NDUFAF6 NM_152416.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 8.14
• Publications: 0 publications found

Genes affected

NDUFAF6 (HGNC:28625): (NADH:ubiquinone oxidoreductase complex assembly factor 6) This gene encodes a protein that localizes to mitochondria and contains a predicted phytoene synthase domain. The encoded protein plays an important role in the assembly of complex I (NADH-ubiquinone oxidoreductase) of the mitochondrial respiratory chain through regulation of subunit ND1 biogenesis. Mutations in this gene are associated with complex I enzymatic deficiency. [provided by RefSeq, Nov 2011]

NDUFAF6 Gene-Disease associations (from GenCC):

• Leigh syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• mitochondrial complex I deficiency, nuclear type 17

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
• primary Fanconi syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Leigh syndrome with leukodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Fanconi renotubular syndrome 5

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 8-95045545-GA-G is Pathogenic according to our data. Variant chr8-95045545-GA-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1064697.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152416.4. 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
	NDUFAF6	NM_152416.4	MANE Select	c.485delA	p.Asn162IlefsTer27	frameshift	Exon 5 of 9	NP_689629.2	Q330K2-1
	NDUFAF6	NM_001354516.2		c.329delA	p.Asn110IlefsTer27	frameshift	Exon 7 of 11	NP_001341445.1	Q330K2-2
	NDUFAF6	NM_001330582.2		c.209delA	p.Asn70IlefsTer27	frameshift	Exon 5 of 9	NP_001317511.1	A0A075B6P0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFAF6	ENST00000396124.9	TSL:2 MANE Select	c.485delA	p.Asn162IlefsTer27	frameshift	Exon 5 of 9	ENSP00000379430.4	Q330K2-1
	NDUFAF6	ENST00000875013.1		c.485delA	p.Asn162IlefsTer27	frameshift	Exon 5 of 9	ENSP00000545072.1
	NDUFAF6	ENST00000940120.1		c.485delA	p.Asn162IlefsTer27	frameshift	Exon 5 of 8	ENSP00000610179.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152006 Hom.: 0 Cov.: 32

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000402 AC: 1 AN: 248968 AF XY: 0.00000740

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 1458384 Hom.: 0 Cov.: 29 AF XY: 0.00000551 AC XY: 4 AN XY: 725762

African (AFR) AF: 0.00 AC: 0 AN: 33394

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26090

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39510

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86138

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53326

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1109210

Other (OTH) AF: 0.0000166 AC: 1 AN: 60252

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152006 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74230

African (AFR) AF: 0.00 AC: 0 AN: 41400

American (AMR) AF: 0.00 AC: 0 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10544

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68002

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Asia WGS AF: 0.000289 AC: 1 AN: 3468

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)
1	-	-	Mitochondrial complex I deficiency, nuclear type 17 (1)
1	-	-	Mitochondrial complex I deficiency, nuclear type 17;C5394473:Fanconi renotubular syndrome 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.1
Mutation Taster		=5/195	disease causing (fs/PTC)

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: rs762093523; hg19: chr8-96057773;