1-234374125-T-G

Position:

• chr1-234374125-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001301733.1(COA6):​c.-121T>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00517 in 1,195,964 control chromosomes in the GnomAD database, including 111 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (42 hom., cov: 31)
  • Exomes 𝑓: 0.0039 (69 hom.)
• Consequence: COA6 NM_001301733.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.06

Genes affected

COA6 (HGNC:18025): (cytochrome c oxidase assembly factor 6) This gene encodes a member of the cytochrome c oxidase subunit 6B family. The encoded protein associates with cytochrome c oxidase may act has an cytochrome c oxidase mitochondrial respiratory complex VI assembly factor. Mutations in this gene may be associated with fatal infantile cardiomyopathy. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Sep 2014]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 1-234374125-T-G is Benign according to our data. Variant chr1-234374125-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 1190954.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0142 (2156/152058) while in subpopulation AFR AF= 0.0443 (1837/41484). AF 95% confidence interval is 0.0426. There are 42 homozygotes in gnomad4. There are 1068 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 42 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COA6	NM_001206641.3	c.213-105T>G		intron_variant		ENST00000366615.10	NP_001193570.2
COA6	NM_001301733.1	c.-121T>G		5_prime_UTR_premature_start_codon_gain_variant	1/2		NP_001288662.1
COA6	NM_001301733.1	c.-121T>G		5_prime_UTR_variant	1/2		NP_001288662.1
COA6	NM_001012985.2	c.123-105T>G		intron_variant			NP_001013003.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COA6	ENST00000366615.10	c.213-105T>G		intron_variant		1	NM_001206641.3	ENSP00000355574.5

Frequencies

GnomAD3 genomes AF: 0.0142 AC: 2153 AN: 151940 Hom.: 43 Cov.: 31

Gnomad AFR AF: 0.0443

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00478

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0210

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.00166

Gnomad OTH AF: 0.0129

GnomAD4 exome AF: 0.00386 AC: 4029 AN: 1043906 Hom.: 69 Cov.: 13 AF XY: 0.00418 AC XY: 2174 AN XY: 520524

Gnomad4 AFR exome AF: 0.0463

Gnomad4 AMR exome AF: 0.00290

Gnomad4 ASJ exome AF: 0.000396

Gnomad4 EAS exome AF: 0.000444

Gnomad4 SAS exome AF: 0.0178

Gnomad4 FIN exome AF: 0.000144

Gnomad4 NFE exome AF: 0.00197

Gnomad4 OTH exome AF: 0.00487

GnomAD4 genome AF: 0.0142 AC: 2156 AN: 152058 Hom.: 42 Cov.: 31 AF XY: 0.0144 AC XY: 1068 AN XY: 74348

Gnomad4 AFR AF: 0.0443

Gnomad4 AMR AF: 0.00478

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000771

Gnomad4 SAS AF: 0.0210

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00166

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.0104 Hom.: 3

Bravo AF: 0.0156

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 11, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	2.2
DANN	Benign	0.48

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: rs867291616; hg19: chr1-234509871; COSMIC: COSV64016925; COSMIC: COSV64016925;