Genetic Variant NDUFA4L2:p.Arg61Leu (chr12-57235774-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001394961.1(NDUFA4L2):c.182G>T(p.Arg61Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000119 in 1,426,674 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R61H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

NDUFA4L2
NM_001394961.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.83

Variant links:

Genes affected

NDUFA4L2 (HGNC:29836): (NDUFA4 mitochondrial complex associated like 2) Predicted to be integral component of membrane. Predicted to be part of mitochondrial respiratory chain complex IV. [provided by Alliance of Genome Resources, Apr 2022]

NDUFA4L2 links:

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ACMG classification

Classification made for transcript

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=0.3190074).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
NDUFA4L2	NM_001394961.1 link	c.182G>T	p.Arg61Leu	missense_variant	Exon 3 of 4	ENST00000554503.6	NP_001381890.1
NDUFA4L2	NM_001394960.1 link	c.182G>T	p.Arg61Leu	missense_variant	Exon 4 of 5		NP_001381889.1
NDUFA4L2	NM_020142.4 link	c.182G>T	p.Arg61Leu	missense_variant	Exon 4 of 5		NP_064527.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NDUFA4L2	ENST00000554503.6 link	c.182G>T	p.Arg61Leu	missense_variant	Exon 3 of 4	1	NM_001394961.1	ENSP00000450664.1	Q9NRX3
NDUFA4L2	ENST00000393825.5 link	c.182G>T	p.Arg61Leu	missense_variant	Exon 4 of 5	1		ENSP00000377411.1	Q9NRX3
NDUFA4L2	ENST00000556732.1 link	c.182G>T	p.Arg61Leu	missense_variant	Exon 3 of 3	3		ENSP00000452193.1	G3V560
NDUFA4L2	ENST00000555173.1 link	n.466G>T		non_coding_transcript_exon_variant	Exon 3 of 4	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000881

AC:

AN:

226994

Hom.:

AF XY:

0.00

AC XY:

AN XY:

121602

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000798

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000119

AC:

AN:

1426674

Hom.:

Cov.:

AF XY:

0.00000993

AC XY:

AN XY:

704962

show subpopulations

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:

0.000184

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.17e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 05, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.182G>T (p.R61L) alteration is located in exon 4 (coding exon 3) of the NDUFA4L2 gene. This alteration results from a G to T substitution at nucleotide position 182, causing the arginine (R) at amino acid position 61 to be replaced by a leucine (L). 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

Benign

0.23

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.20

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.31

T;T;T

Eigen

Benign

-0.12

Eigen_PC

Benign

-0.22

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.82

.;T;D

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.32

T;T;T

MetaSVM

Benign

-0.47

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-3.9

D;D;D

REVEL

Benign

0.25

Sift

Uncertain

0.0070

D;D;D

Sift4G

Uncertain

0.042

D;D;D

Polyphen

0.98

D;D;.

Vest4

0.51

MutPred

0.29

Loss of disorder (P = 0.046);Loss of disorder (P = 0.046);Loss of disorder (P = 0.046);

MVP

0.78

MPC

0.052

ClinPred

0.83

GERP RS

1.6

Varity_R

0.32

gMVP

0.30

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