chr2-201079018-G-A

Position:

• chr2-201079018-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002491.3(NDUFB3):​c.136G>A​(p.Gly46Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000055 in 1,454,990 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: NDUFB3 NM_002491.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.79

Genes affected

NDUFB3 (HGNC:7698): (NADH:ubiquinone oxidoreductase subunit B3) This gene encodes an accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) which is the first enzyme in the electron transport chain of mitochondria. This protein localizes to the inner membrane of the mitochondrion as a single-pass membrane protein. Mutations in this gene contribute to mitochondrial complex 1 deficiency. Alternative splicing results in multiple transcript variants encoding the same protein. Humans have multiple pseudogenes of this gene. [provided by RefSeq, Mar 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3473165).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NDUFB3	NM_002491.3	c.136G>A	p.Gly46Ser	missense_variant	2/3	ENST00000237889.9	NP_002482.1
NDUFB3	NM_001257102.2	c.136G>A	p.Gly46Ser	missense_variant	3/4		NP_001244031.1
NDUFB3	XM_011511230.4	c.136G>A	p.Gly46Ser	missense_variant	3/4		XP_011509532.1
NDUFB3	XM_047444488.1	c.136G>A	p.Gly46Ser	missense_variant	3/4		XP_047300444.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NDUFB3	ENST00000237889.9	c.136G>A	p.Gly46Ser	missense_variant	2/3	1	NM_002491.3	ENSP00000237889	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000550 AC: 8 AN: 1454990 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 723858

Gnomad4 AFR exome AF: 0.0000303

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental cataract;C0036572:Seizure;C1836830:Developmental regression;C1843392:Death in childhood Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Diagnostics Services (NGS), CSIR - Centre For Cellular And Molecular Biology

Dec 20, 2019

The c.136G>A variant is not present in publicly available databases like 1000 Genomes, Exome Variant Server (EVS), Exome Aggregation Consortium (ExAC), Genome Aggregation Database (gnomAD), dbSNP and our in-house database. The variant was also not reported to OMIM, ClinVar and Human Genome Mutation Database (HGMD) in any other affected individuals. Predictions from different in-silico pathogenicity prediction programs like SIFT, Polyphen, MutationTaster2, CADD etc. are contradictory. No functional studies were conducted. Due to lack of enough evidence for the variant's pathogenicity and also considering the phenotype of the patient the variant has been classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.0084	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.015	.;T;T;T
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.96	D;.;.;D
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.35	T;T;T;T
MetaSVM	Benign	-0.68	T
MutationTaster	Benign	0.81	N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.29	N;N;N;N
REVEL	Benign	0.20
Sift	Benign	0.099	T;T;T;T
Sift4G	Benign	0.43	T;T;T;T
Polyphen		0.70	.;P;P;P
Vest4		0.39
MutPred		0.35		Gain of glycosylation at P44 (P = 0.0758);Gain of glycosylation at P44 (P = 0.0758);Gain of glycosylation at P44 (P = 0.0758);Gain of glycosylation at P44 (P = 0.0758);
MVP		0.84
MPC		0.44
ClinPred		0.97	D
GERP RS		4.2
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.42
gMVP		0.67

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: rs1575544444; hg19: chr2-201943741;