Variant X-47142352-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001135998.3(NDUFB11):c.427G>A(p.Asp143Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000091 in 1,208,819 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D143H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 2 hem., cov: 23)

Exomes 𝑓: 0.0000082 ( 0 hom. 3 hem. )

Consequence

NDUFB11
NM_001135998.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.16

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High Hemizygotes in GnomAd at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NDUFB11	NM_001135998.3 linkuse as main transcript	c.427G>A	p.Asp143Asn	missense_variant	3/3	ENST00000377811.4
NDUFB11	NM_019056.7 linkuse as main transcript	c.457G>A	p.Asp153Asn	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NDUFB11	ENST00000377811.4 linkuse as main transcript	c.427G>A	p.Asp143Asn	missense_variant	3/3	1	NM_001135998.3	P1	Q9NX14-1

Frequencies

GnomAD3 genomes

AF:

0.0000179

AC:

AN:

111512

Hom.:

Cov.:

AF XY:

0.0000593

AC XY:

AN XY:

33710

show subpopulations

Gnomad AFR

AF:

0.0000653

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000555

AC:

AN:

180153

Hom.:

AF XY:

0.00

AC XY:

AN XY:

64795

show subpopulations

Gnomad AFR exome

AF:

0.0000771

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000820

AC:

AN:

1097307

Hom.:

Cov.:

AF XY:

0.00000827

AC XY:

AN XY:

362743

show subpopulations

Gnomad4 AFR exome

AF:

0.000114

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000356

Gnomad4 OTH exome

AF:

0.0000651

GnomAD4 genome

AF:

0.0000179

AC:

AN:

111512

Hom.:

Cov.:

AF XY:

0.0000593

AC XY:

AN XY:

33710

show subpopulations

Gnomad4 AFR

AF:

0.0000653

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000340

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Mitochondrial complex 1 deficiency, nuclear type 30

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Johns Hopkins Genomics, Johns Hopkins University

Jun 13, 2019

This NDUFB11 variant has not been reported in ClinVar nor the literature, to our knowledge. Additionally, this variant (rs374083393) is rare (<0.1%) in a large population dataset (gnomAD: 1/201877 total alleles; 0.0004945%; no homozygotes; no hemizygotes). Two bioinformatic tool queried predict that this substitution would be probably damaging, and the aspartic acid residue at this position is evolutionarily conserved across all species assessed. Bioinformatic analysis predicts that this missense variant would not affect normal exon 3 splicing, although this has not been confirmed experimentally to our knowledge. The clinical significance of c.457G>A is uncertain at this time. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.37

Cadd

Benign

Dann

Pathogenic

1.0

DEOGEN2

Uncertain

0.64

D;.

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.87

D;D

M_CAP

Uncertain

0.15

MetaRNN

Uncertain

0.69

D;D

MetaSVM

Uncertain

-0.11

MutationAssessor

Uncertain

2.6

M;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-4.0

D;D

REVEL

Uncertain

0.39

Sift

Benign

0.064

T;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.61

MVP

0.83

MPC

1.1

ClinPred

0.94

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.68

gMVP

0.68

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over