12-50112316-A-G

Variant names:

• chr12-50112316-A-G
• rs974992601
• NM_032901.4:c.-9+15A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001257134.2(COX14):​c.-190A>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 0.0000375 in 985,480 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000037 (0 hom.)
• Consequence: COX14 NM_001257134.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.91
• Publications: 0 publications found

Genes affected

COX14 (HGNC:28216): (cytochrome c oxidase assembly factor COX14) This gene encodes a small single-pass transmembrane protein that localizes to mitochondria. This protein may play a role in coordinating the early steps of cytochrome c oxidase (COX; also known as complex IV) subunit assembly and, in particular, the synthesis and assembly of the COX I subunit of the holoenzyme. Mutations in this gene have been associated with mitochondrial complex IV deficiency. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2012]

COX14 Gene-Disease associations (from GenCC):

• cytochrome-c oxidase deficiency disease

  Inheritance: AR, Unknown Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• mitochondrial complex IV deficiency, nuclear type 10

  Inheritance: AR Classification: LIMITED Submitted by: G2P
• mitochondrial disease

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ENSG00000295262 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 12-50112316-A-G is Benign according to our data. Variant chr12-50112316-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 388877.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001257134.2. 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
	COX14	NM_032901.4	MANE Select	c.-9+15A>G		intron	N/A	NP_116290.1	Q96I36
	COX14	NM_001257134.2		c.-190A>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 2	NP_001244063.1	Q96I36
	COX14	NM_001257134.2		c.-190A>G		5_prime_UTR	Exon 1 of 2	NP_001244063.1	Q96I36

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COX14	ENST00000550487.6	TSL:1 MANE Select	c.-9+15A>G		intron	N/A	ENSP00000446524.1	Q96I36
	COX14	ENST00000548985.1	TSL:2	c.-190A>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 2	ENSP00000447776.1	Q96I36
	COX14	ENST00000548985.1	TSL:2	c.-190A>G		5_prime_UTR	Exon 1 of 2	ENSP00000447776.1	Q96I36

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152160 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.0000735

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000372 AC: 31 AN: 833202 Hom.: 0 Cov.: 29 AF XY: 0.0000338 AC XY: 13 AN XY: 384790

African (AFR) AF: 0.00 AC: 0 AN: 15788

American (AMR) AF: 0.00 AC: 0 AN: 984

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5154

East Asian (EAS) AF: 0.00 AC: 0 AN: 3632

South Asian (SAS) AF: 0.00 AC: 0 AN: 16464

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 282

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1622

European-Non Finnish (NFE) AF: 0.0000341 AC: 26 AN: 761976

Other (OTH) AF: 0.000183 AC: 5 AN: 27300

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152278 Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4 AN XY: 74458

African (AFR) AF: 0.00 AC: 0 AN: 41560

American (AMR) AF: 0.00 AC: 0 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000378

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	1.0
DANN	Benign	0.67
PhyloP100		-1.9
PromoterAI		-0.014	Neutral

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: rs974992601; hg19: chr12-50506099;