Genetic Variant NM_001863.5:c.-145G>A (chr19-35648270-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001863.5(COX6B1):c.-145G>A variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0973 in 153,178 control chromosomes in the GnomAD database, including 785 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.097 ( 776 hom., cov: 32)

Exomes 𝑓: 0.12 ( 9 hom. )

Consequence

COX6B1
NM_001863.5 upstream_gene

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.66

Variant links:

Genes affected

COX6B1 (HGNC:2280): (cytochrome c oxidase subunit 6B1) Cytochrome c oxidase (COX), the terminal enzyme of the mitochondrial respiratory chain, catalyzes the electron transfer from reduced cytochrome c to oxygen. It is a heteromeric complex consisting of 3 catalytic subunits encoded by mitochondrial genes and multiple structural subunits encoded by nuclear genes. The mitochondrially-encoded subunits function in electron transfer, and the nuclear-encoded subunits may be involved in the regulation and assembly of the complex. This nuclear gene encodes subunit VIb. Mutations in this gene are associated with severe infantile encephalomyopathy. Three pseudogenes COX6BP-1, COX6BP-2 and COX6BP-3 have been found on chromosomes 7, 17 and 22q13.1-13.2, respectively. [provided by RefSeq, Jan 2010]

COX6B1 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.64).

BP6

Variant 19-35648270-G-A is Benign according to our data. Variant chr19-35648270-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 328837.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.134 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COX6B1	NM_001863.5 link	c.-145G>A		upstream_gene_variant		ENST00000649813.2	NP_001854.1	P14854

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COX6B1	ENST00000649813.2 link	c.-145G>A		upstream_gene_variant			NM_001863.5	ENSP00000497926.1		P14854

Frequencies

GnomAD3 genomes

AF:

0.0971

AC:

14778

AN:

152138

Hom.:

773

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0934

Gnomad AMI

AF:

0.211

Gnomad AMR

AF:

0.139

Gnomad ASJ

AF:

0.0421

Gnomad EAS

AF:

0.136

Gnomad SAS

AF:

0.0951

Gnomad FIN

AF:

0.113

Gnomad MID

AF:

0.0475

Gnomad NFE

AF:

0.0864

Gnomad OTH

AF:

0.0918

GnomAD4 exome

AF:

0.119

AC:

110

AN:

922

Hom.:

Cov.:

AF XY:

0.124

AC XY:

AN XY:

574

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.177

Gnomad4 SAS exome

AF:

0.113

Gnomad4 FIN exome

AF:

0.500

Gnomad4 NFE exome

AF:

0.111

Gnomad4 OTH exome

AF:

0.0455

GnomAD4 genome

AF:

0.0972

AC:

14799

AN:

152256

Hom.:

776

Cov.:

AF XY:

0.0993

AC XY:

7393

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.0936

Gnomad4 AMR

AF:

0.139

Gnomad4 ASJ

AF:

0.0421

Gnomad4 EAS

AF:

0.136

Gnomad4 SAS

AF:

0.0952

Gnomad4 FIN

AF:

0.113

Gnomad4 NFE

AF:

0.0864

Gnomad4 OTH

AF:

0.0918

Alfa

AF:

0.0862

Hom.:

589

Bravo

AF:

0.101

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 18, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mitochondrial complex IV deficiency, nuclear type 1

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.64

CADD

Benign

DANN

Benign

0.90

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over