rs786205225

Positions:

• chrX-47142690-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The ENST00000377811.4(NDUFB11):​c.262C>T​(p.Arg88Ter) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: NDUFB11 ENST00000377811.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 3.76

Genes affected

NDUFB11 (HGNC:20372): (NADH:ubiquinone oxidoreductase subunit B11) The protein encoded by this gene is a subunit of the multisubunit NADH:ubiquinone oxidoreductase (complex I). Mammalian complex I is located at the mitochondrial inner membrane. This protein has NADH dehydrogenase activity and oxidoreductase activity. It transfers electrons from NADH to ubiquinone. Mutations in the human gene are associated with linear skin defects with multiple congenital anomalies 3 and mitochondrial complex I deficiency. [provided by RefSeq, Dec 2016]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 9 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-47142690-G-A is Pathogenic according to our data. Variant chrX-47142690-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 190302.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-47142690-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NDUFB11	NM_001135998.3	c.262C>T	p.Arg88Ter	stop_gained	2/3	ENST00000377811.4	NP_001129470.1
NDUFB11	NM_019056.7	c.262C>T	p.Arg88Ter	stop_gained	2/3		NP_061929.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NDUFB11	ENST00000377811.4	c.262C>T	p.Arg88Ter	stop_gained	2/3	1	NM_001135998.3	ENSP00000367042	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Linear skin defects with multiple congenital anomalies 3 Pathogenic:1 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 02, 2015	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Histiocytoid cardiomyopathy Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

Aug 15, 2016

- -

Linear skin defects with multiple congenital anomalies 1;C4225421:Linear skin defects with multiple congenital anomalies 3;CN257533:Mitochondrial complex I deficiency, nuclear type 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 25, 2016

The R88X variant in the NDUFB11 gene has been reported previously as a de novo change in twofemale patients, one with MLS syndrome and histiocytoid cardiomyopathy in whom R88X wasidentified in the mosaic state in lymphocytes (van Rahden et al., 2015), and another with histiocytoidcardiomyopathy who lacked diagnostic features of MLS (Rea et al., 2016a; Rea et al., 2016b). Thisvariant is predicted to cause loss of normal protein function either through protein truncation ornonsense-mediated mRNA decay. The R88X variant was not observed in approximately 6500individuals of European and African American ancestry in the NHLBI Exome Sequencing Project,indicating it is not a common benign variant in these populations. We interpret R88X as a pathogenicvariant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	34
DANN	Uncertain	1.0
FATHMM_MKL	Benign	0.71	D
MutationTaster	Benign	1.0	A;A
Vest4		0.55
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs786205225; hg19: chrX-47002089;