Genetic Variant NDUFB11:p.Glu121Lys (chrX-47142418-C-T) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_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

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 5.16

Publications

11 publications found

Variant links:

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

NDUFB11 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 372149.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001135998.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFB11	NM_001135998.3	MANE Select	c.361G>A	p.Glu121Lys	missense	Exon 3 of 3	NP_001129470.1	Q9NX14-1
	NDUFB11	NM_019056.7		c.391G>A	p.Glu131Lys	missense	Exon 3 of 3	NP_061929.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NDUFB11	ENST00000377811.4	TSL:1 MANE Select	c.361G>A	p.Glu121Lys	missense	Exon 3 of 3	ENSP00000367042.3	Q9NX14-1
NDUFB11	ENST00000276062.9	TSL:1	c.*18G>A		3_prime_UTR	Exon 3 of 3	ENSP00000276062.9	A0A8J8YU24
NDUFB11	ENST00000687244.1		c.391G>A	p.Glu131Lys	missense	Exon 3 of 3	ENSP00000509334.1	Q9NX14-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Linear skin defects with multiple congenital anomalies 3 (1)

Linear skin defects with multiple congenital anomalies 3;C4746985:Mitochondrial complex I deficiency, nuclear type 30 (1)

Mitochondrial complex I deficiency, nuclear type 30 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.77

BayesDel_addAF

Pathogenic

0.51

BayesDel_noAF

Pathogenic

0.49

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.77

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.92

M_CAP

Uncertain

0.16

MetaRNN

Pathogenic

0.93

MetaSVM

Uncertain

-0.044

MutationAssessor

Pathogenic

3.4

PhyloP100

5.2

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-3.8

REVEL

Uncertain

0.58

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.92

MutPred

0.78

Gain of MoRF binding (P = 0.0084)

MVP

0.97

MPC

1.2

ClinPred

1.0

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.99

gMVP

0.98

Mutation Taster

=5/95

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over