12-57235754-A-G

Variant names:

• chr12-57235754-A-G
• rs761964545
• NM_001394961.1:c.202T>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001394961.1(COXFA4L2):​c.202T>C​(p.Tyr68His) variant causes a missense change. The variant allele was found at a frequency of 0.00000125 in 1,593,738 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: COXFA4L2 NM_001394961.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.07
• Publications: 0 publications found

Genes affected

COXFA4L2 (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]

ENSG00000295078 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.845

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001394961.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COXFA4L2	NM_001394961.1	MANE Select	c.202T>C	p.Tyr68His	missense	Exon 3 of 4	NP_001381890.1	Q9NRX3
	COXFA4L2	NM_001394960.1		c.202T>C	p.Tyr68His	missense	Exon 4 of 5	NP_001381889.1	Q9NRX3
	COXFA4L2	NM_020142.4		c.202T>C	p.Tyr68His	missense	Exon 4 of 5	NP_064527.1	Q9NRX3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFA4L2	ENST00000554503.6	TSL:1 MANE Select	c.202T>C	p.Tyr68His	missense	Exon 3 of 4	ENSP00000450664.1	Q9NRX3
	NDUFA4L2	ENST00000393825.5	TSL:1	c.202T>C	p.Tyr68His	missense	Exon 4 of 5	ENSP00000377411.1	Q9NRX3
	NDUFA4L2	ENST00000909958.1		c.358T>C	p.Tyr120His	missense	Exon 4 of 5	ENSP00000580017.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152042 Hom.: 0 Cov.: 33

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000416 AC: 1 AN: 240444 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000920

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.94e-7 AC: 1 AN: 1441696 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 714264

African (AFR) AF: 0.00 AC: 0 AN: 32928

American (AMR) AF: 0.00 AC: 0 AN: 43420

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25070

East Asian (EAS) AF: 0.00 AC: 0 AN: 39312

South Asian (SAS) AF: 0.00 AC: 0 AN: 84600

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52914

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5662

European-Non Finnish (NFE) AF: 9.10e-7 AC: 1 AN: 1098398

Other (OTH) AF: 0.00 AC: 0 AN: 59392

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152042 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74230

African (AFR) AF: 0.00 AC: 0 AN: 41378

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68000

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	0.20	D
PhyloP100		7.1
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-4.1	D
REVEL	Pathogenic	0.83
Sift	Benign	0.096	T
Sift4G	Benign	0.14	T
Polyphen		1.0	D
Vest4		0.86
MutPred		0.76		Loss of phosphorylation at Y68 (P = 0.0302)
MVP		0.77
MPC		0.22
ClinPred		0.98	D
GERP RS		4.4
Varity_R		0.42
gMVP		0.44
Mutation Taster		=75/25	polymorphism

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

Other links and lift over

dbSNP: rs761964545; hg19: chr12-57629537;