NM_198076.6:c.43-124G>A

Variant names:

• chr1-244841820-G-A
• rs146116444
• NM_198076.6:c.43-124G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_198076.6(COX20):​c.43-124G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00243 in 613,630 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0020 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (7 hom.)
• Consequence: COX20 NM_198076.6 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.676
• Publications: 0 publications found

Genes affected

COX20 (HGNC:26970): (cytochrome c oxidase assembly factor COX20) This gene encodes a protein that plays a role in the assembly of cytochrome C oxidase, an important component of the respiratory pathway. It contains two transmembrane helices and localizes to the mitochondrial membrane. Mutations in this gene can cause mitochondrial complex IV deficiency, which results in ataxia and muscle hypotonia. There are multiple pseudogenes for this gene. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2015]

HNRNPU (HGNC:5048): (heterogeneous nuclear ribonucleoprotein U) This gene encodes a member of a family of proteins that bind nucleic acids and function in the formation of ribonucleoprotein complexes in the nucleus with heterogeneous nuclear RNA (hnRNA). The encoded protein has affinity for both RNA and DNA, and binds scaffold-attached region (SAR) DNA. Mutations in this gene have been associated with epileptic encephalopathy, early infantile, 54. A pseudogene of this gene has been identified on chromosome 14. [provided by RefSeq, Jun 2017]

HNRNPU Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• developmental and epileptic encephalopathy, 54

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 1-244841820-G-A is Benign according to our data. Variant chr1-244841820-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1203374.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00202 (308/152294) while in subpopulation NFE AF = 0.0024 (163/68022). AF 95% confidence interval is 0.0021. There are 1 homozygotes in GnomAd4. There are 178 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 7 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198076.6. 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
	COX20	NM_198076.6	MANE Select	c.43-124G>A		intron	N/A	NP_932342.1	Q5RI15-1
	COX20	NM_001312872.1		c.79-124G>A		intron	N/A	NP_001299801.1	B3KM21
	COX20	NM_001312871.1		c.43-124G>A		intron	N/A	NP_001299800.1	Q5RI15-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COX20	ENST00000411948.7	TSL:1 MANE Select	c.43-124G>A		intron	N/A	ENSP00000406327.2	Q5RI15-1
	COX20	ENST00000391839.6	TSL:1	n.102-375G>A		intron	N/A
	COX20	ENST00000366528.3	TSL:2	c.79-124G>A		intron	N/A	ENSP00000355486.3	Q5RI15-2

Frequencies

GnomAD3 genomes AF: 0.00202 AC: 308 AN: 152176 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0118

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00240

Gnomad OTH AF: 0.00143

GnomAD4 exome AF: 0.00257 AC: 1185 AN: 461336 Hom.: 7 Cov.: 5 AF XY: 0.00248 AC XY: 605 AN XY: 244214

African (AFR) AF: 0.000479 AC: 6 AN: 12534

American (AMR) AF: 0.000381 AC: 7 AN: 18378

Ashkenazi Jewish (ASJ) AF: 0.0000728 AC: 1 AN: 13744

East Asian (EAS) AF: 0.0000320 AC: 1 AN: 31258

South Asian (SAS) AF: 0.000195 AC: 8 AN: 41064

European-Finnish (FIN) AF: 0.0123 AC: 523 AN: 42572

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1978

European-Non Finnish (NFE) AF: 0.00211 AC: 578 AN: 273844

Other (OTH) AF: 0.00235 AC: 61 AN: 25964

GnomAD4 genome AF: 0.00202 AC: 308 AN: 152294 Hom.: 1 Cov.: 32 AF XY: 0.00239 AC XY: 178 AN XY: 74478

African (AFR) AF: 0.000217 AC: 9 AN: 41570

American (AMR) AF: 0.000458 AC: 7 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.0118 AC: 125 AN: 10608

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

European-Non Finnish (NFE) AF: 0.00240 AC: 163 AN: 68022

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00641 Hom.: 0

Bravo AF: 0.000816

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.63
DANN	Benign	0.66
PhyloP100		-0.68
Mutation Taster		=100/0	polymorphism

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: rs146116444; hg19: chr1-245005122;