Genetic Variant NDUFAB1:p.Lys137Asn (chr16-23582344-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005003.3(NDUFAB1):c.411G>C(p.Lys137Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000506 in 1,580,206 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000049 ( 0 hom. )

Consequence

NDUFAB1
NM_005003.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.08

Variant links:

Genes affected

NDUFAB1 (HGNC:7694): (NADH:ubiquinone oxidoreductase subunit AB1) Predicted to enable acyl binding activity; acyl carrier activity; and fatty acid binding activity. Involved in mitochondrial respiratory chain complex I assembly and protein lipoylation. Located in mitochondrion and nucleoplasm. Part of mitochondrial respiratory chain complex I. Colocalizes with mitochondrial large ribosomal subunit. [provided by Alliance of Genome Resources, Apr 2022]

NDUFAB1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFAB1	NM_005003.3 link	c.411G>C	p.Lys137Asn	missense_variant	Exon 4 of 5	ENST00000007516.8	NP_004994.1
NDUFAB1	XM_011545856.3 link	c.504G>C	p.Lys168Asn	missense_variant	Exon 5 of 6		XP_011544158.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFAB1	ENST00000007516.8 link	c.411G>C	p.Lys137Asn	missense_variant	Exon 4 of 5	1	NM_005003.3	ENSP00000007516.2		O14561

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152064

Hom.:

Cov.:

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:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000490

AC:

AN:

1428142

Hom.:

Cov.:

AF XY:

0.00000423

AC XY:

AN XY:

708442

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000161

Gnomad4 EAS exome

AF:

0.0000510

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.12e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152064

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74282

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000113

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 21, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.411G>C (p.K137N) alteration is located in exon 4 (coding exon 4) of the NDUFAB1 gene. This alteration results from a G to C substitution at nucleotide position 411, causing the lysine (K) at amino acid position 137 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.83

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.44

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

T;T;.

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.95

.;D;D

M_CAP

Benign

0.029

MetaRNN

Uncertain

0.43

T;T;T

MetaSVM

Benign

-0.88

MutationAssessor

Benign

1.4

L;L;.

PrimateAI

Uncertain

0.72

PROVEAN

Uncertain

-4.0

D;.;.

REVEL

Benign

0.23

Sift

Benign

0.067

T;.;.

Sift4G

Uncertain

0.042

D;D;T

Polyphen

0.99

D;D;.

Vest4

0.67

MutPred

0.53

Loss of methylation at K137 (P = 0.0204);Loss of methylation at K137 (P = 0.0204);.;

MVP

0.60

MPC

1.0

ClinPred

0.99

GERP RS

2.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.63

gMVP

0.74

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over