rs1057519073

chrX-47142418-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_001135998.3(NDUFB11):c.361G>A(p.Glu121Lys) variant causes a missense 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: NDUFB11 NM_001135998.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 5.16

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 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.93
• PP5: Variant X-47142418-C-T is Pathogenic according to our data. Variant chrX-47142418-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 372149.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-47142418-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NDUFB11	NM_001135998.3	c.361G>A	p.Glu121Lys	missense_variant	3/3	ENST00000377811.4
NDUFB11	NM_019056.7	c.391G>A	p.Glu131Lys	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NDUFB11	ENST00000377811.4	c.361G>A	p.Glu121Lys	missense_variant	3/3	1	NM_001135998.3	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 07, 2023	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25772934, 26741492, 31243186, 28050600, 30423443, 27488349, 36675256, 33233646, 31332208) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 05, 2023	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 131 of the NDUFB11 protein (p.Glu131Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of NDUFB11-related conditions (PMID: 26741492, 31243186, 36252119). In at least one individual the variant was observed to be de novo. This variant is also known as p.E121K. ClinVar contains an entry for this variant (Variation ID: 372149). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects NDUFB11 function (PMID: 26741492). For these reasons, this variant has been classified as Pathogenic. -

Mitochondrial complex 1 deficiency, nuclear type 30 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 13, 2018

- -

Linear skin defects with multiple congenital anomalies 3 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Feb 02, 2022

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 X-linked dominant linear skin defects with multiple congenital anomalies 3 (MIM#300952) and X-linked recessive nuclear type 30 mitochondrial complex I deficiency (MIM#301021). Affected females have been reported with heterozygous null alleles, whereas affected males have only been identified with missense and single residue in-frame deletions, suggesting that some residual enzyme activity is required for males to be viable, whereas complete loss of function variants may be lethal when hemizygous (PMID: 30423443). (I) 0110 - This gene is associated with X-linked disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. Affected females have previously been reported to inherit pathogenic variants from their unaffected mothers. It has been suggested that this may be due to patterns of somatic X-chromosome inactivation, mosaicism or additional genetic and external factors (PMID: 28050600). (I) 0115 - Variants in this gene are known to have variable expressivity. Variable syndromic features have been observed in affected individuals. However, anaemia and cardiomyopathy appear to be consistent features in males and females, respectively (PMID: 28050600, PMID: 30423443, PMID: 27488349). (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated ESSS subunit of NADH:ubiquinone oxidoreductase (complex I) (NCBI). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. The variant has previously been classified as pathogenic in ClinVar, and has been reported de novo in a hemizygous male with lethal infantile mitochondrial disorder (PMID: 26741492). Additionally, the variant has been observed in a mother and daughter affected with left ventricular noncompaction (PMID: 31243186); it was not considered to be causative as they did not present with a metabolic disorder, however, the mitochondrial features of NDUFB11-related disease are known to only present in hemizygous males (PMID: 25772934, PMID: 30423443). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. Western blots using patient fibroblasts demonstrated no detectable NDUFB11 protein, consistent with a complete loss of function (PMID: 26741492). (SP) 1207 - Parental origin of the variant is unresolved. Testing of this individual's mother did not confirm maternal inheritance. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
Cadd	Uncertain	25
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.77	D;.
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Uncertain	-0.044	T
MutationAssessor	Pathogenic	3.4	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.8	D;D
REVEL	Uncertain	0.58
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.92
MutPred		0.78		Gain of MoRF binding (P = 0.0084);.;
MVP		0.97
MPC		1.2
ClinPred		1.0	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.99
gMVP		0.98

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

Publications

LitVar

Other links and lift over

dbSNP: rs1057519073; hg19: chrX-47001817; COSMIC: COSV52101747; COSMIC: COSV52101747;