20-31639921-TTG-T

Position:

• chr20-31639921-TTG-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 BS2

The NM_032609.3(COX4I2):​c.83-8_83-7del variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0075 in 1,613,788 control chromosomes in the GnomAD database, including 72 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0048 (3 hom., cov: 31)
  • Exomes 𝑓: 0.0078 (69 hom.)
• Consequence: COX4I2 NM_032609.3 splice_polypyrimidine_tract, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 1.18

Genes affected

COX4I2 (HGNC:16232): (cytochrome c oxidase subunit 4I2) 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 isoform 2 of subunit IV. Isoform 1 of subunit IV is encoded by a different gene, however, the two genes show a similar structural organization. Subunit IV is the largest nuclear encoded subunit which plays a pivotal role in COX regulation. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP6: Variant 20-31639921-TTG-T is Benign according to our data. Variant chr20-31639921-TTG-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 338032.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=2, Uncertain_significance=1}.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COX4I2	NM_032609.3	c.83-8_83-7del		splice_polypyrimidine_tract_variant, intron_variant		ENST00000376075.4	NP_115998.2
COX4I2	XM_005260579.5	c.98-8_98-7del		splice_polypyrimidine_tract_variant, intron_variant			XP_005260636.1
COX4I2	XM_005260580.5	c.98-8_98-7del		splice_polypyrimidine_tract_variant, intron_variant			XP_005260637.1
COX4I2	XM_005260581.4	c.83-8_83-7del		splice_polypyrimidine_tract_variant, intron_variant			XP_005260638.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COX4I2	ENST00000376075.4	c.83-8_83-7del		splice_polypyrimidine_tract_variant, intron_variant		1	NM_032609.3	ENSP00000365243	P1
COX4I2	ENST00000490030.1	n.113-8_113-7del		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00481 AC: 731 AN: 152082 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.00186

Gnomad AMI AF: 0.0593

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00123

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00774

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00478 AC: 1201 AN: 251034 Hom.: 6 AF XY: 0.00494 AC XY: 671 AN XY: 135716

Gnomad AFR exome AF: 0.00197

Gnomad AMR exome AF: 0.00200

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00346

Gnomad FIN exome AF: 0.00274

Gnomad NFE exome AF: 0.00803

Gnomad OTH exome AF: 0.00342

GnomAD4 exome AF: 0.00778 AC: 11377 AN: 1461588 Hom.: 69 AF XY: 0.00770 AC XY: 5600 AN XY: 727088

Gnomad4 AFR exome AF: 0.00182

Gnomad4 AMR exome AF: 0.00226

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00312

Gnomad4 FIN exome AF: 0.00264

Gnomad4 NFE exome AF: 0.00945

Gnomad4 OTH exome AF: 0.00469

GnomAD4 genome AF: 0.00480 AC: 731 AN: 152200 Hom.: 3 Cov.: 31 AF XY: 0.00465 AC XY: 346 AN XY: 74402

Gnomad4 AFR AF: 0.00185

Gnomad4 AMR AF: 0.00236

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.00123

Gnomad4 NFE AF: 0.00774

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00569 Hom.: 0

Bravo AF: 0.00495

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	COX4I2: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 12, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 09, 2024	- -

Pancreatic insufficiency-anemia-hyperostosis syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

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: rs528430338; hg19: chr20-30227724;