1-52687760-T-G

Variant names:

• chr1-52687760-T-G
• rs443751
• NM_023077.3:c.656A>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_023077.3(COA7):​c.656A>C​(p.Lys219Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign 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. K219R) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: COA7 NM_023077.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.99
• Publications: 36 publications found

Genes affected

COA7 (HGNC:25716): (cytochrome c oxidase assembly factor 7) Located in mitochondrial intermembrane space and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

COA7 Gene-Disease associations (from GenCC):

• spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 3

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a chain Cytochrome c oxidase assembly factor 7 (size 229) in uniprot entity COA7_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_023077.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29564077).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_023077.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COA7	NM_023077.3	MANE Select	c.656A>C	p.Lys219Thr	missense	Exon 3 of 3	NP_075565.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COA7	ENST00000371538.5	TSL:1 MANE Select	c.656A>C	p.Lys219Thr	missense	Exon 3 of 3	ENSP00000360593.3
	COA7	ENST00000486918.1	TSL:3	n.710A>C		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 54

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 41731

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0068	T
Eigen	Benign	-0.15
Eigen_PC	Benign	0.0028
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.0089	T
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.4	L
PhyloP100		2.0
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.11
Sift	Benign	0.28	T
Sift4G	Benign	0.25	T
Polyphen		0.14	B
Vest4		0.20
MutPred		0.31		Loss of methylation at K219 (P = 0.0226)
MVP		0.47
MPC		0.18
ClinPred		0.21	T
GERP RS		5.5
Varity_R		0.068
gMVP		0.48
Mutation Taster		=87/13	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: rs443751; hg19: chr1-53153432;