X-47142420-C-T

Variant names:

• chrX-47142420-C-T
• rs782753177
• NM_001135998.3:c.359G>A

Variant summary

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

The NM_001135998.3(NDUFB11):​c.359G>A​(p.Arg120His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000264 in 1,209,942 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 9 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000063 (0 hom., 2 hem., cov: 23)
  • Exomes 𝑓: 0.000023 (0 hom. 7 hem.)
• Consequence: NDUFB11 NM_001135998.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.56

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 -4 ACMG points.

• BS2: High Hemizygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFB11	NM_001135998.3	c.359G>A	p.Arg120His	missense_variant	Exon 3 of 3	ENST00000377811.4	NP_001129470.1
NDUFB11	NM_019056.7	c.389G>A	p.Arg130His	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.359G>A	p.Arg120His	missense_variant	Exon 3 of 3	1	NM_001135998.3	ENSP00000367042.3

Frequencies

GnomAD3 genomes AF: 0.0000626 AC: 7 AN: 111818 Hom.: 0 Cov.: 23 AF XY: 0.0000588 AC XY: 2 AN XY: 33986

Gnomad AFR AF: 0.0000651

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000947

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000740

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000376

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000273 AC: 5 AN: 183167 Hom.: 0 AF XY: 0.0000296 AC XY: 2 AN XY: 67621

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000157

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000228 AC: 25 AN: 1098124 Hom.: 0 Cov.: 31 AF XY: 0.0000193 AC XY: 7 AN XY: 363488

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000284

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000662

Gnomad4 SAS exome AF: 0.000148

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000154

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome AF: 0.0000626 AC: 7 AN: 111818 Hom.: 0 Cov.: 23 AF XY: 0.0000588 AC XY: 2 AN XY: 33986

Gnomad4 AFR AF: 0.0000651

Gnomad4 AMR AF: 0.0000947

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000740

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000376

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000718

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Linear skin defects with multiple congenital anomalies 1 Uncertain:1

Apr 27, 2019

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Sep 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 130 of the NDUFB11 protein (p.Arg130His). This variant is present in population databases (rs782753177, gnomAD 0.02%). This missense change has been observed in individual(s) with NDUFB11-related conditions (PMID: 34490615). ClinVar contains an entry for this variant (Variation ID: 638355). 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	0.17
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Pathogenic	0.25
CADD	Uncertain	23
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.77	D;.
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.46	T;T
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Pathogenic	3.4	M;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-4.6	D;D
REVEL	Uncertain	0.42
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.47
MutPred		0.78		Loss of MoRF binding (P = 0.0116);.;
MVP		0.94
MPC		1.3
ClinPred		0.91	D
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.93
gMVP		0.89

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: rs782753177; hg19: chrX-47001819;