rs1057519073

Variant names:

• chrX-47142418-C-T
• rs1057519073
• NM_001135998.3:c.361G>A

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS3 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 (★★). ClinVar reports functional evidence for this variant: "SCV004269346: Experimental studies have shown that this missense change affects NDUFB11 function (PMID:26741492)." and additional evidence is available in ClinVar.

• Frequency: Genomes: not found (cov: 23)
• Consequence: NDUFB11 NM_001135998.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 5.16
• Publications: 11 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 16 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV004269346: Experimental studies have shown that this missense change affects NDUFB11 function (PMID: 26741492).; SCV002557187: "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)."
• 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

Sel.	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.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)
1	-	-	Linear skin defects with multiple congenital anomalies 3 (1)
1	-	-	Linear skin defects with multiple congenital anomalies 3;C4746985:Mitochondrial complex I deficiency, nuclear type 30 (1)
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	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
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	-0.044	T
MutationAssessor	Pathogenic	3.4	M
PhyloP100		5.2
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.58
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	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
Mutation Taster		=5/95	disease causing (ClinVar)

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

Other links and lift over

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