12-57235754-A-C

Variant names:

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

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>G​(p.Tyr68Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000139 in 1,441,696 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y68H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: COXFA4L2 NM_001394961.1 missense
• Clinical Significance: Not reported in ClinVar
• 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, 0.88

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>G	p.Tyr68Asp	missense	Exon 3 of 4	NP_001381890.1	Q9NRX3
	COXFA4L2	NM_001394960.1		c.202T>G	p.Tyr68Asp	missense	Exon 4 of 5	NP_001381889.1	Q9NRX3
	COXFA4L2	NM_020142.4		c.202T>G	p.Tyr68Asp	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>G	p.Tyr68Asp	missense	Exon 3 of 4	ENSP00000450664.1	Q9NRX3
	NDUFA4L2	ENST00000393825.5	TSL:1	c.202T>G	p.Tyr68Asp	missense	Exon 4 of 5	ENSP00000377411.1	Q9NRX3
	NDUFA4L2	ENST00000909958.1		c.358T>G	p.Tyr120Asp	missense	Exon 4 of 5	ENSP00000580017.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1441696 Hom.: 0 Cov.: 31 AF XY: 0.00000280 AC XY: 2 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: 0.0000236 AC: 2 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: 0.00 AC: 0 AN: 1098398

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

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.46	T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	0.23	D
PhyloP100		7.1
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-9.1	D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.046	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.69		Gain of disorder (P = 0.0091)
MVP		0.87
MPC		0.24
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.86
gMVP		0.63
Mutation Taster		=72/28	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;