chrX-47142364-A-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_001135998.3(NDUFB11):c.415T>G(p.Ser139Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000413 in 1,209,551 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S139F) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.0000036 ( 0 hom. 2 hem. )

Consequence

NDUFB11
NM_001135998.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 3.10

Publications

0 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.2475316).

BP6

Variant X-47142364-A-C is Benign according to our data. Variant chrX-47142364-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1437660.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

BS2

High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFB11	NM_001135998.3 link	c.415T>G	p.Ser139Ala	missense_variant	Exon 3 of 3	ENST00000377811.4	NP_001129470.1	Q9NX14-1
NDUFB11	NM_019056.7 link	c.445T>G	p.Ser149Ala	missense_variant	Exon 3 of 3		NP_061929.2	Q9NX14-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFB11	ENST00000377811.4 link	c.415T>G	p.Ser139Ala	missense_variant	Exon 3 of 3	1	NM_001135998.3	ENSP00000367042.3		Q9NX14-1

Frequencies

GnomAD3 genomes

AF:

0.00000895

AC:

AN:

111672

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000364

AC:

AN:

1097879

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

363255

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26400

American (AMR)

AF:

0.00

AC:

AN:

35192

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19382

East Asian (EAS)

AF:

0.00

AC:

AN:

30201

South Asian (SAS)

AF:

0.00

AC:

AN:

54082

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40388

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4133

European-Non Finnish (NFE)

AF:

0.00000475

AC:

AN:

842017

Other (OTH)

AF:

0.00

AC:

AN:

46084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000895

AC:

AN:

111672

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33836

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30700

American (AMR)

AF:

0.00

AC:

AN:

10512

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2646

East Asian (EAS)

AF:

0.00

AC:

AN:

3562

South Asian (SAS)

AF:

0.00

AC:

AN:

2663

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6083

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53082

Other (OTH)

AF:

0.00

AC:

AN:

1502

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Dec 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces serine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 149 of the NDUFB11 protein (p.Ser149Ala). This variant is present in population databases (rs199837826, gnomAD 0.001%). This variant has not been reported in the literature in individuals affected with NDUFB11-related conditions. ClinVar contains an entry for this variant (Variation ID: 1437660). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Sep 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NDUFB11: BP4 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.087

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.30

T;.

FATHMM_MKL

Benign

0.56

LIST_S2

Benign

0.59

T;T

M_CAP

Benign

0.015

MetaRNN

Benign

0.25

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Uncertain

2.5

M;.

PhyloP100

3.1

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-1.1

N;N

REVEL

Benign

0.10

Sift

Benign

0.38

T;T

Sift4G

Uncertain

0.052

T;T

Polyphen

0.82

P;P

Vest4

0.26

MutPred

0.46

Loss of disorder (P = 0.0446);.;

MVP

0.71

MPC

0.93

ClinPred

0.52

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.44

gMVP

0.48

Mutation Taster

=96/4

polymorphism

(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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chrX-47142364-A-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over