7-43639604-C-T

Variant names:

• chr7-43639604-C-T
• rs868303769
• NM_018224.4:c.419G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_018224.4(COA1):​c.419G>A​(p.Gly140Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,660 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (1 hom.)
• Consequence: COA1 NM_018224.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.11
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04758188).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018224.4. 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
	COA1	NM_018224.4	MANE Select	c.419G>A	p.Gly140Asp	missense	Exon 6 of 6	NP_060694.2	Q9GZY4
	COA1	NM_001321197.2		c.419G>A	p.Gly140Asp	missense	Exon 7 of 7	NP_001308126.1	Q9GZY4
	COA1	NM_001321198.2		c.419G>A	p.Gly140Asp	missense	Exon 7 of 7	NP_001308127.1	Q9GZY4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COA1	ENST00000223336.11	TSL:2 MANE Select	c.419G>A	p.Gly140Asp	missense	Exon 6 of 6	ENSP00000223336.6	Q9GZY4
	COA1	ENST00000395879.5	TSL:1	c.419G>A	p.Gly140Asp	missense	Exon 5 of 5	ENSP00000379218.1	Q9GZY4
	COA1	ENST00000896980.1		c.437G>A	p.Gly146Asp	missense	Exon 7 of 7	ENSP00000567039.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251454 AF XY: 0.00000736

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: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461660 Hom.: 1 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727142

African (AFR) AF: 0.0000896 AC: 3 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111828

Other (OTH) AF: 0.0000662 AC: 4 AN: 60384

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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	Benign	0.094
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	0.56
DANN	Benign	0.31
DEOGEN2	Benign	0.018	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.45	T
M_CAP	Benign	0.00093	T
MetaRNN	Benign	0.048	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.89	L
PhyloP100		-1.1
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.41	N
REVEL	Benign	0.0080
Sift	Benign	0.18	T
Sift4G	Benign	0.20	T
Polyphen		0.011	B
Vest4		0.10
MutPred		0.14		Gain of helix (P = 0.0225)
MVP		0.29
MPC		0.31
ClinPred		0.019	T
GERP RS		-0.52
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.028
gMVP		0.18
Mutation Taster		=92/8	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: rs868303769; hg19: chr7-43679203;