8-95052195-G-A

Variant names:

• chr8-95052195-G-A
• rs61743028
• NM_152416.4:c.838G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_152416.4(NDUFAF6):​c.838G>A​(p.Val280Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00309 in 1,614,070 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0028 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (35 hom.)
• Consequence: NDUFAF6 NM_152416.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 6.34
• 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 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009096205).
• BP6: Variant 8-95052195-G-A is Benign according to our data. Variant chr8-95052195-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136605.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0028 (426/152282) while in subpopulation AMR AF = 0.00549 (84/15296). AF 95% confidence interval is 0.00454. There are 4 homozygotes in GnomAd4. There are 196 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR,AD gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFAF6	NM_152416.4	MANE Select	c.838G>A	p.Val280Ile	missense	Exon 8 of 9	NP_689629.2
	NDUFAF6	NM_001354516.2		c.682G>A	p.Val228Ile	missense	Exon 10 of 11	NP_001341445.1
	NDUFAF6	NM_001330582.2		c.562G>A	p.Val188Ile	missense	Exon 8 of 9	NP_001317511.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFAF6	ENST00000396124.9	TSL:2 MANE Select	c.838G>A	p.Val280Ile	missense	Exon 8 of 9	ENSP00000379430.4
	NDUFAF6	ENST00000396111.6	TSL:5	c.562G>A	p.Val188Ile	missense	Exon 9 of 10	ENSP00000379417.1
	NDUFAF6	ENST00000396113.5	TSL:5	c.562G>A	p.Val188Ile	missense	Exon 14 of 15	ENSP00000379419.1

Frequencies

GnomAD3 genomes AF: 0.00280 AC: 426 AN: 152164 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000700

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00550

Gnomad ASJ AF: 0.0156

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.00323

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.00354 AC: 884 AN: 249396 AF XY: 0.00377

Gnomad AFR exome AF: 0.000323

Gnomad AMR exome AF: 0.00379

Gnomad ASJ exome AF: 0.0143

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000232

Gnomad NFE exome AF: 0.00432

Gnomad OTH exome AF: 0.00727

GnomAD4 exome AF: 0.00312 AC: 4556 AN: 1461788 Hom.: 35 Cov.: 31 AF XY: 0.00321 AC XY: 2333 AN XY: 727200

African (AFR) AF: 0.00248 AC: 83 AN: 33480

American (AMR) AF: 0.00445 AC: 199 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0142 AC: 371 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00192 AC: 166 AN: 86256

European-Finnish (FIN) AF: 0.000300 AC: 16 AN: 53394

Middle Eastern (MID) AF: 0.0473 AC: 273 AN: 5768

European-Non Finnish (NFE) AF: 0.00280 AC: 3114 AN: 1111960

Other (OTH) AF: 0.00553 AC: 334 AN: 60388

GnomAD4 genome AF: 0.00280 AC: 426 AN: 152282 Hom.: 4 Cov.: 32 AF XY: 0.00263 AC XY: 196 AN XY: 74456

African (AFR) AF: 0.000698 AC: 29 AN: 41548

American (AMR) AF: 0.00549 AC: 84 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0156 AC: 54 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4832

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10612

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.00323 AC: 220 AN: 68018

Other (OTH) AF: 0.00568 AC: 12 AN: 2114

Alfa AF: 0.00419 Hom.: 13

Bravo AF: 0.00350

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00464 AC: 38

ExAC AF: 0.00348 AC: 421

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.00605

EpiControl AF: 0.00676

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NDUFAF6: BP4, BS2

Jul 14, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 19, 2018

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not specified Benign:1

Dec 17, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Mitochondrial complex I deficiency, nuclear type 17 Benign:1

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mitochondrial complex I deficiency, nuclear type 17;C5394473:Fanconi renotubular syndrome 5 Benign:1

Jan 17, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.17
Eigen_PC	Benign	0.0059
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.0091	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.8	L
PhyloP100		6.3
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.34	N
REVEL	Benign	0.10
Sift	Benign	0.43	T
Sift4G	Benign	0.21	T
Polyphen		0.0050	B
Vest4		0.27
MVP		0.19
MPC		0.14
ClinPred		0.013	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.046
gMVP		0.39
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs61743028; hg19: chr8-96064423;