X-47142364-A-C

Variant names:

• chrX-47142364-A-C
• rs199837826
• NM_001135998.3:c.415T>G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

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. 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: 𝑓 0.0000090 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.0000036 (0 hom. 2 hem.)
• Consequence: NDUFB11 NM_001135998.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 3.10

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]

ACMG classification

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: {Likely_benign=1, Uncertain_significance=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	c.415T>G	p.Ser139Ala	missense_variant	Exon 3 of 3	ENST00000377811.4	NP_001129470.1
NDUFB11	NM_019056.7	c.445T>G	p.Ser149Ala	missense_variant	Exon 3 of 3		NP_061929.2

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00000895 AC: 1 AN: 111672 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33836

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

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

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:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign: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

Other links and lift over

dbSNP: rs199837826; hg19: chrX-47001763;