7-43648608-A-G

Position:

• chr7-43648608-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018224.4(COA1):​c.7T>C​(p.Trp3Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,220 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: COA1 NM_018224.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.04

Genes affected

COA1 (HGNC:21868): (cytochrome c oxidase assembly factor 1) Involved in mitochondrial cytochrome c oxidase assembly and mitochondrial respiratory chain complex I assembly. Located in cytosol and mitochondrion. Is integral component of mitochondrial inner membrane. [provided by Alliance of Genome Resources, Apr 2022]

STK17A (HGNC:11395): (serine/threonine kinase 17a) This gene is a member of the DAP kinase-related apoptosis-inducing protein kinase family and encodes an autophosphorylated nuclear protein with a protein kinase domain. The protein has apoptosis-inducing activity. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13126713).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COA1	NM_018224.4	c.7T>C	p.Trp3Arg	missense_variant	2/6	ENST00000223336.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COA1	ENST00000223336.11	c.7T>C	p.Trp3Arg	missense_variant	2/6	2	NM_018224.4	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152220 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 29

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152220 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74370

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 21, 2023

The c.7T>C (p.W3R) alteration is located in exon 2 (coding exon 1) of the COA1 gene. This alteration results from a T to C substitution at nucleotide position 7, causing the tryptophan (W) at amino acid position 3 to be replaced by an arginine (R). 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	Uncertain	0.37
BayesDel_addAF	Benign	-0.090	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	19
DANN	Benign	0.77
DEOGEN2	Benign	0.026	T;T;T;.;T;.
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.36	T;.;.;T;T;T
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.13	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L;L;L;.;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.78	N;N;N;N;N;.
REVEL	Benign	0.087
Sift	Pathogenic	0.0	D;D;D;D;D;.
Sift4G	Pathogenic	0.0	D;D;D;.;D;.
Polyphen		0.99	D;D;D;.;.;.
Vest4		0.43
MutPred		0.33		Gain of methylation at W3 (P = 0.0199);Gain of methylation at W3 (P = 0.0199);Gain of methylation at W3 (P = 0.0199);Gain of methylation at W3 (P = 0.0199);Gain of methylation at W3 (P = 0.0199);Gain of methylation at W3 (P = 0.0199);
MVP		0.64
MPC		1.1
ClinPred		0.72	D
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs1300534563; hg19: chr7-43688207;