Genetic Variant NM_001086521.2:c.195+271C>T (chr17-81239949-C-T) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_001086521.2(NDUFAF8):c.195+271C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000729 in 536,514 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00061 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00078 ( 0 hom. )

Consequence

NDUFAF8
NM_001086521.2 intron

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: -0.0100

Variant links:

Genes affected

NDUFAF8 (HGNC:33551): (NADH:ubiquinone oxidoreductase complex assembly factor 8) Involved in mitochondrial respiratory chain complex I assembly. Located in mitochondrion. Implicated in nuclear type mitochondrial complex I deficiency 34. [provided by Alliance of Genome Resources, Apr 2022]

NDUFAF8 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 17-81239949-C-T is Pathogenic according to our data. Variant chr17-81239949-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 691642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-81239949-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
NDUFAF8	NM_001086521.2 link	c.195+271C>T	intron_variant	Intron 2 of 2	ENST00000431388.3	NP_001079990.1	A1L188
NDUFAF8	NM_001353402.1 link	c.199+267C>T	intron_variant	Intron 2 of 2		NP_001340331.1
NDUFAF8	NM_001353403.1 link	c.37+6C>T	splice_region_variant, intron_variant	Intron 2 of 2		NP_001340332.1
NDUFAF8	NR_148426.1 link	n.36C>T	non_coding_transcript_exon_variant	Exon 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFAF8	ENST00000431388.3 link	c.195+271C>T		intron_variant	Intron 2 of 2	1	NM_001086521.2	ENSP00000400184.2		A1L188

Frequencies

GnomAD3 genomes

AF:

0.000611

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

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:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00121

Gnomad OTH

AF:

0.000955

GnomAD4 exome

AF:

0.000775

AC:

298

AN:

384294

Hom.:

Cov.:

AF XY:

0.000863

AC XY:

175

AN XY:

202684

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000677

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000740

Gnomad4 NFE exome

AF:

0.00104

Gnomad4 OTH exome

AF:

0.00160

GnomAD4 genome

AF:

0.000611

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.000457

AC XY:

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.000145

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.00121

Gnomad4 OTH

AF:

0.000955

Alfa

AF:

0.000953

Hom.:

Bravo

AF:

0.000601

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mitochondrial complex 1 deficiency, nuclear type 34

Pathogenic:5

Mar 30, 2022

Undiagnosed Diseases Network, NIH

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 30, 2022

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 07, 2020

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Feb 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with mitochondrial complex I deficiency, nuclear type 34 (MIM#618776). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0209 - Splice site variant proven to affect splicing of the transcript with uncertain effect on protein sequence. Functional analysis of patient fibroblasts shows this variant results in intron retention and the loss of isoform 2. However, the exact protein outcome is unclear as this would be expected to result in a truncated protein (PMID: 31866046). (SP) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (93 heterozygotes, 0 homozygotes). (SP) 0705 - No comparable intronic variants have previous evidence for pathogenicity. (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been described as likely pathogenic and pathogenic, and observed in two unrelated compound heterozygous individuals with Leigh syndrome and complex I deficiency (ClinVar, PMID: 31866046). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

May 21, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: C17ORF89 (NDUFAF8) c.195+271C>T is located at a position not widely known to affect splicing. However, several computational tools predict a significant impact on normal splicing: Three predict the variant strengthens a cryptic intronic 5 donor site. Experimental evidence demonstrated this variant was associated with an mRNA defect leading to loss of the functionally relevant transcript (Alston_2020). The variant allele was found at a frequency of 0.00062 in 150992 control chromosomes, predominantly at a frequency of 0.0012 within the Non-Finnish European subpopulation in the gnomAD v3.1.1 database. Due to an unknown prevalence of C17ORF89 associated Mitochondrial Complex 1 Deficiency, this frequency relative to that expected for a pathogenic variant in C17ORF89 is unknown, allowing no conclusion about variant significance. c.195+271C>T has been reported in the literature in two comprehensively genotyped compound heterozygous individuals affected with Mitochondrial Complex 1 Deficiency (Alston_2020). Experimental evidence derived from studies on fibroblasts and muscle cells from one of these individuals indicated a decrease in complex I activity, a reduction in oxidative capacity, decreased levels of fully assembled complex I and a generalized reduction in complex I subunits (Alston_2020). These data indicate that the variant may be associated with disease. Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

NDUFAF8-related disorder

Pathogenic:1

Jun 06, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The NDUFAF8 c.199+267C>T variant is predicted to interfere with splicing. This variant, also reported as c.195+271C>T in transcript NM_001086521, has been reported in two unrelated individuals with a clinical diagnosis of Leigh syndrome (subjects 1 and 2, Alston et al. 2019. PubMed ID: 31866046). In vitro studies from subject 1's fibroblast cells demonstrated expression of this variant results in aberrant splicing, a reduction in oxidative capacity, as well as decreased levels of fully assembled complex I in both muscle cells and fibroblasts compared to controls (Figures S3, S4 and 3, Alston et al. 2019. PubMed ID: 31866046). Additionally, a rescue assay demonstrated that this phenotype could be corrected by a reintroduction of wildtype (Figure 3, Alston et al. 2019. PubMed ID: 31866046). This variant is reported in 0.12% of alleles in individuals of European (non-Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic. -

Mitochondrial disease

Pathogenic:1

Oct 09, 2019

Wellcome Centre for Mitochondrial Research, Newcastle University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:1

Aug 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NDUFAF8: PM3:Strong, PM2, PS3:Supporting -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

2.5

DANN

Benign

0.73

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.28

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.28

Position offset: -6

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over