X-47142364-A-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BP6

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). 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
• 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 Likely_benign. Variant got -3 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}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NDUFB11	NM_001135998.3	c.415T>G	p.Ser139Ala	missense_variant	3/3	ENST00000377811.4
NDUFB11	NM_019056.7	c.445T>G	p.Ser149Ala	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NDUFB11	ENST00000377811.4	c.415T>G	p.Ser139Ala	missense_variant	3/3	1	NM_001135998.3	P1

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

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2022	NDUFB11: BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 23, 2023	This variant is present in population databases (rs199837826, gnomAD 0.001%). 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. 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. ClinVar contains an entry for this variant (Variation ID: 1437660). This variant has not been reported in the literature in individuals affected with NDUFB11-related conditions. 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). -

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;.
MutationTaster	Benign	0.99	N;N
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;