rs201088736

Variant names:

• chr8-95045599-G-C
• rs201088736
• NM_152416.4:c.532G>C

Your query was ambiguous. Multiple possible variants found:

• chr8-95045599-G-C
• chr8-95045599-G-A
• chr8-95045599-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PS3 PP3 PP5

The NM_152416.4(NDUFAF6):​c.532G>C​(p.Ala178Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000992 in 1,613,410 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 Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV002072924: Functional studies revealed a damaging effect." and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: NDUFAF6 NM_152416.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7 U:3
• Conservation: PhyloP100: 4.28
• Publications: 7 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: Likely_pathogenic. The variant received 6 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002072924: Functional studies revealed a damaging effect.; SCV005040518: The most pronounced variant effect results in significantly reduced normal complex I activity in patients fibroblasts, which was rescued by normal C8ORF38 (Bianciardi_2016). PMID: 27623250
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.813
• PP5: Variant 8-95045599-G-C is Pathogenic according to our data. Variant chr8-95045599-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 372254.

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.532G>C	p.Ala178Pro	missense	Exon 5 of 9	NP_689629.2	Q330K2-1
	NDUFAF6	NM_001354516.2		c.376G>C	p.Ala126Pro	missense	Exon 7 of 11	NP_001341445.1	Q330K2-2
	NDUFAF6	NM_001330582.2		c.256G>C	p.Ala86Pro	missense	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.532G>C	p.Ala178Pro	missense	Exon 5 of 9	ENSP00000379430.4	Q330K2-1
	NDUFAF6	ENST00000875013.1		c.532G>C	p.Ala178Pro	missense	Exon 5 of 9	ENSP00000545072.1
	NDUFAF6	ENST00000940120.1		c.532G>C	p.Ala178Pro	missense	Exon 5 of 8	ENSP00000610179.1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000112 AC: 28 AN: 249340 AF XY: 0.000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000194

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000105 AC: 154 AN: 1461240 Hom.: 0 Cov.: 30 AF XY: 0.000116 AC XY: 84 AN XY: 726962

African (AFR) AF: 0.00 AC: 0 AN: 33458

American (AMR) AF: 0.0000671 AC: 3 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39536

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.000112 AC: 6 AN: 53380

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5762

European-Non Finnish (NFE) AF: 0.000123 AC: 137 AN: 1111678

Other (OTH) AF: 0.000116 AC: 7 AN: 60360

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152170 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74324

African (AFR) AF: 0.0000241 AC: 1 AN: 41446

American (AMR) AF: 0.0000654 AC: 1 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68026

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.000118 Hom.: 0

Bravo AF: 0.0000756

ESP6500AA AF: 0.000275 AC: 1

ESP6500EA AF: 0.000123 AC: 1

ExAC AF: 0.000166 AC: 20

EpiCase AF: 0.000273

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
5	-	-	Mitochondrial complex I deficiency, nuclear type 17 (5)
2	1	-	not provided (3)
-	1	-	Inborn genetic diseases (1)
-	1	-	See cases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.046	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Uncertain	-0.086	T
MutationAssessor	Pathogenic	3.3	M
PhyloP100		4.3
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-4.2	D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.99	D
Vest4		0.88
MVP		0.83
MPC		0.79
ClinPred		0.86	D
GERP RS		4.9
Varity_R		0.97
gMVP		0.95
Mutation Taster		=5/95	disease causing (ClinVar)

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: rs201088736; hg19: chr8-96057827;