rs786205225

Variant names:

• chrX-47142690-G-A
• rs786205225
• NM_001135998.3:c.262C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-47142690-G-A
• chrX-47142690-G-C

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001135998.3(NDUFB11):​c.262C>T​(p.Arg88*) 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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 23)
• Consequence: NDUFB11 NM_001135998.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 3.76
• Publications: 5 publications found

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]

NDUFB11 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• linear skin defects with multiple congenital anomalies 3

  Inheritance: XL Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• mitochondrial complex I deficiency, nuclear type 30

  Inheritance: XL Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• linear skin defects with multiple congenital anomalies

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFB11	NM_001135998.3	c.262C>T	p.Arg88*	stop_gained	Exon 2 of 3	ENST00000377811.4	NP_001129470.1
NDUFB11	NM_019056.7	c.262C>T	p.Arg88*	stop_gained	Exon 2 of 3		NP_061929.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFB11	ENST00000377811.4	c.262C>T	p.Arg88*	stop_gained	Exon 2 of 3	1	NM_001135998.3	ENSP00000367042.3

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

Apr 02, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Histiocytoid cardiomyopathy Pathogenic:1

Aug 15, 2016

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

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

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

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Jul 25, 2016

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		3.8
Vest4		0.55
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=8/192	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs786205225; hg19: chrX-47002089;