X-47142364-A-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_001135998.3(NDUFB11):ā€‹c.415T>Gā€‹(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. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: š‘“ 0.0000090 ( 0 hom., 0 hem., cov: 22)
Exomes š‘“: 0.0000036 ( 0 hom. 2 hem. )

Consequence

NDUFB11
NM_001135998.3 missense

Scores

4
13

Clinical Significance

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

Conservation

PhyloP100: 3.10
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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
NDUFB11NM_001135998.3 linkc.415T>G p.Ser139Ala missense_variant Exon 3 of 3 ENST00000377811.4 NP_001129470.1 Q9NX14-1
NDUFB11NM_019056.7 linkc.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
NDUFB11ENST00000377811.4 linkc.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:
1
AN:
111672
Hom.:
0
Cov.:
22
AF XY:
0.00
AC XY:
0
AN XY:
33836
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:
4
AN:
1097879
Hom.:
0
Cov.:
31
AF XY:
0.00000551
AC XY:
2
AN XY:
363255
show subpopulations
Gnomad4 AFR exome
AF:
0.00
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:
0.00000475
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000895
AC:
1
AN:
111672
Hom.:
0
Cov.:
22
AF XY:
0.00
AC XY:
0
AN XY:
33836
show subpopulations
Gnomad4 AFR
AF:
0.00
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:
0.0000188
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378
ExAC
AF:
0.0000165
AC:
2

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
Sep 01, 2022
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

NDUFB11: BP4 -

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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.087
T
BayesDel_noAF
Benign
-0.36
CADD
Benign
18
DANN
Uncertain
0.99
DEOGEN2
Benign
0.30
T;.
FATHMM_MKL
Benign
0.56
D
LIST_S2
Benign
0.59
T;T
M_CAP
Benign
0.015
T
MetaRNN
Benign
0.25
T;T
MetaSVM
Benign
-0.98
T
MutationAssessor
Uncertain
2.5
M;.
PrimateAI
Uncertain
0.50
T
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
D
GERP RS
4.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.44
gMVP
0.48

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.

Other links and lift over

dbSNP: rs199837826; hg19: chrX-47001763; API