rs397514584

Variant names:

• chrX-77902641-A-G
• rs397514584
• NM_001866.3:c.41-2A>G

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001866.3(COX7B):​c.41-2A>G variant causes a splice acceptor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 23)
• Consequence: COX7B NM_001866.3 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 5.62
• Publications: 3 publications found

Genes affected

COX7B (HGNC:2291): (cytochrome c oxidase subunit 7B) Cytochrome c oxidase (COX), the terminal component of the mitochondrial respiratory chain, catalyzes the electron transfer from reduced cytochrome c to oxygen. This component 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 function in the regulation and assembly of the complex. This nuclear gene encodes subunit VIIb, which is highly similar to bovine COX VIIb protein and is found in all tissues. This gene may have several pseudogenes on chromosomes 1, 2, 20 and 22. [provided by RefSeq, Jun 2011]

COX7B Gene-Disease associations (from GenCC):

• linear skin defects with multiple congenital anomalies 2

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• linear skin defects with multiple congenital anomalies

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 12, offset of -1, new splice context is: cttttttcgttttcctgtAGgtt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-77902641-A-G is Pathogenic according to our data. Variant chrX-77902641-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 39768.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COX7B	NM_001866.3	c.41-2A>G		splice_acceptor_variant, intron_variant	Intron 1 of 2	ENST00000650309.2	NP_001857.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COX7B	ENST00000650309.2	c.41-2A>G		splice_acceptor_variant, intron_variant	Intron 1 of 2		NM_001866.3	ENSP00000497474.1
COX7B	ENST00000373335.4	c.-20-2A>G		splice_acceptor_variant, intron_variant	Intron 2 of 3	2		ENSP00000496880.1
COX7B	ENST00000475465.1	c.41-2A>G		splice_acceptor_variant, intron_variant	Intron 1 of 1	2		ENSP00000497958.1
COX7B	ENST00000647835.1	c.41-9A>G		intron_variant	Intron 1 of 2			ENSP00000497517.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Linear skin defects with multiple congenital anomalies 2 Pathogenic:1 Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Nov 02, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	34
DANN	Uncertain	0.99
FATHMM_MKL	Uncertain	0.87	D
PhyloP100		5.6
GERP RS		4.9
Mutation Taster		=8/92	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		1.0		Position offset: 1
DS_AL_spliceai		0.98		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs397514584; hg19: chrX-77158138;