8-95041772-C-T

Variant names:

• chr8-95041772-C-T
• rs7818382
• NM_152416.4:c.477+146C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_152416.4(NDUFAF6):​c.477+146C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.473 in 711,900 control chromosomes in the GnomAD database, including 82,625 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (14677 hom., cov: 31)
  • Exomes 𝑓: 0.48 (67948 hom.)
• Consequence: NDUFAF6 NM_152416.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0330
• Publications: 18 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

ENSG00000287322 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 8-95041772-C-T is Benign according to our data. Variant chr8-95041772-C-T is described in ClinVar as Benign. ClinVar VariationId is 1181913.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.67 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFAF6	NM_152416.4	c.477+146C>T		intron_variant	Intron 4 of 8	ENST00000396124.9	NP_689629.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFAF6	ENST00000396124.9	c.477+146C>T		intron_variant	Intron 4 of 8	2	NM_152416.4	ENSP00000379430.4

Frequencies

GnomAD3 genomes AF: 0.429 AC: 65152 AN: 151796 Hom.: 14676 Cov.: 31

Gnomad AFR AF: 0.295

Gnomad AMI AF: 0.531

Gnomad AMR AF: 0.497

Gnomad ASJ AF: 0.500

Gnomad EAS AF: 0.690

Gnomad SAS AF: 0.558

Gnomad FIN AF: 0.450

Gnomad MID AF: 0.446

Gnomad NFE AF: 0.457

Gnomad OTH AF: 0.453

GnomAD4 exome AF: 0.485 AC: 271528 AN: 559986 Hom.: 67948 AF XY: 0.491 AC XY: 147738 AN XY: 301152

African (AFR) AF: 0.290 AC: 4567 AN: 15728

American (AMR) AF: 0.538 AC: 17655 AN: 32790

Ashkenazi Jewish (ASJ) AF: 0.499 AC: 9223 AN: 18500

East Asian (EAS) AF: 0.687 AC: 21556 AN: 31386

South Asian (SAS) AF: 0.565 AC: 34122 AN: 60366

European-Finnish (FIN) AF: 0.453 AC: 18647 AN: 41180

Middle Eastern (MID) AF: 0.497 AC: 1184 AN: 2384

European-Non Finnish (NFE) AF: 0.459 AC: 150441 AN: 328108

Other (OTH) AF: 0.478 AC: 14133 AN: 29544

GnomAD4 genome AF: 0.429 AC: 65187 AN: 151914 Hom.: 14677 Cov.: 31 AF XY: 0.434 AC XY: 32196 AN XY: 74240

African (AFR) AF: 0.295 AC: 12219 AN: 41412

American (AMR) AF: 0.497 AC: 7595 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.500 AC: 1732 AN: 3466

East Asian (EAS) AF: 0.689 AC: 3565 AN: 5172

South Asian (SAS) AF: 0.560 AC: 2698 AN: 4820

European-Finnish (FIN) AF: 0.450 AC: 4738 AN: 10534

Middle Eastern (MID) AF: 0.439 AC: 129 AN: 294

European-Non Finnish (NFE) AF: 0.457 AC: 31071 AN: 67930

Other (OTH) AF: 0.454 AC: 959 AN: 2112

Alfa AF: 0.449 Hom.: 5936

Bravo AF: 0.429

Asia WGS AF: 0.564 AC: 1961 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	6.2
DANN	Benign	0.54
PhyloP100		-0.033
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs7818382; hg19: chr8-96054000;