X-47142371-G-C

Variant names:

• chrX-47142371-G-C
• rs782327477
• NM_001135998.3:c.408C>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001135998.3(NDUFB11):​c.408C>G​(p.Ile136Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000373 in 1,097,916 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 14 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000037 (0 hom. 14 hem.)
• Consequence: NDUFB11 NM_001135998.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.940
• Publications: 0 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2373972).
• BS2: High Hemizygotes in GnomAdExome4 at 14 XL gene

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.408C>G	p.Ile136Met	missense	Exon 3 of 3	NP_001129470.1	Q9NX14-1
	NDUFB11	NM_019056.7		c.438C>G	p.Ile146Met	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.408C>G	p.Ile136Met	missense	Exon 3 of 3	ENSP00000367042.3	Q9NX14-1
	NDUFB11	ENST00000276062.9	TSL:1	c.*65C>G		3_prime_UTR	Exon 3 of 3	ENSP00000276062.9	A0A8J8YU24
	NDUFB11	ENST00000687244.1		c.438C>G	p.Ile146Met	missense	Exon 3 of 3	ENSP00000509334.1	Q9NX14-2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.0000164 AC: 3 AN: 182420 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000368

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000373 AC: 41 AN: 1097916 Hom.: 0 Cov.: 31 AF XY: 0.0000385 AC XY: 14 AN XY: 363290

African (AFR) AF: 0.00 AC: 0 AN: 26401

American (AMR) AF: 0.00 AC: 0 AN: 35194

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19383

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30204

South Asian (SAS) AF: 0.00 AC: 0 AN: 54109

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4136

European-Non Finnish (NFE) AF: 0.0000404 AC: 34 AN: 842002

Other (OTH) AF: 0.000130 AC: 6 AN: 46087

GnomAD4 genome Cov.: 23

Alfa AF: 0.000142 Hom.: 1

Bravo AF: 0.0000227

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	14
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.0090	T
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.94
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.40	N
REVEL	Benign	0.081
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.026	D
Polyphen		0.87	P
Vest4		0.20
MutPred		0.65		Gain of disorder (P = 0.0106)
MVP		0.31
MPC		0.97
ClinPred		0.15	T
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.47
gMVP		0.42
Mutation Taster		=92/8	polymorphism

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: rs782327477; hg19: chrX-47001770;