14-73491111-C-A

Position:

• chr14-73491111-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_024644.5(RIOX1):​c.94C>A​(p.Leu32Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00306 in 1,606,864 control chromosomes in the GnomAD database, including 110 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (45 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (65 hom.)
• Consequence: RIOX1 NM_024644.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.687

Genes affected

RIOX1 (HGNC:20968): (ribosomal oxygenase 1) Predicted to enable histone H3-methyl-lysine-36 demethylase activity; histone H3-methyl-lysine-4 demethylase activity; and iron ion binding activity. Predicted to be involved in histone lysine demethylation; negative regulation of osteoblast differentiation; and negative regulation of transcription, DNA-templated. Located in nucleolus. [provided by Alliance of Genome Resources, Apr 2022]

HEATR4 (HGNC:16761): (HEAT repeat containing 4) Predicted to enable oxidoreductase activity. [provided by Alliance of Genome Resources, Apr 2022]

ACOT1 (HGNC:33128): (acyl-CoA thioesterase 1) Enables acyl-CoA hydrolase activity. Involved in acyl-CoA metabolic process; long-chain fatty acid metabolic process; and very long-chain fatty acid metabolic process. Located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

HEATR4 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0034736693).
• BP6: Variant 14-73491111-C-A is Benign according to our data. Variant chr14-73491111-C-A is described in ClinVar as [Benign]. Clinvar id is 768664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0135 (2055/152348) while in subpopulation AFR AF= 0.044 (1832/41592). AF 95% confidence interval is 0.0424. There are 45 homozygotes in gnomad4. There are 988 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 45 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RIOX1	NM_024644.5	c.94C>A	p.Leu32Met	missense_variant	1/1	ENST00000304061.8	NP_078920.2
HEATR4	NM_001220484.1	c.2844+1955G>T		intron_variant		ENST00000553558.6	NP_001207413.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RIOX1	ENST00000304061.8	c.94C>A	p.Leu32Met	missense_variant	1/1	6	NM_024644.5	ENSP00000477507.1
HEATR4	ENST00000553558.6	c.2844+1955G>T		intron_variant		2	NM_001220484.1	ENSP00000450444.2
HEATR4	ENST00000334988.2	c.2844+1955G>T		intron_variant		1		ENSP00000335447.2
HEATR4	ENST00000565094.1	n.25+645G>T		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.0135 AC: 2049 AN: 152230 Hom.: 44 Cov.: 33

Gnomad AFR AF: 0.0440

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00608

Gnomad ASJ AF: 0.0219

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.0115

GnomAD3 exomes AF: 0.00400 AC: 958 AN: 239778 Hom.: 10 AF XY: 0.00328 AC XY: 429 AN XY: 130800

Gnomad AFR exome AF: 0.0433

Gnomad AMR exome AF: 0.00221

Gnomad ASJ exome AF: 0.0191

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000690

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000477

Gnomad OTH exome AF: 0.00207

GnomAD4 exome AF: 0.00197 AC: 2865 AN: 1454516 Hom.: 65 Cov.: 84 AF XY: 0.00177 AC XY: 1283 AN XY: 723376

Gnomad4 AFR exome AF: 0.0494

Gnomad4 AMR exome AF: 0.00256

Gnomad4 ASJ exome AF: 0.0196

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000118

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000246

Gnomad4 OTH exome AF: 0.00511

GnomAD4 genome AF: 0.0135 AC: 2055 AN: 152348 Hom.: 45 Cov.: 33 AF XY: 0.0133 AC XY: 988 AN XY: 74498

Gnomad4 AFR AF: 0.0440

Gnomad4 AMR AF: 0.00607

Gnomad4 ASJ AF: 0.0219

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000441

Gnomad4 OTH AF: 0.0113

Alfa AF: 0.00274 Hom.: 5

Bravo AF: 0.0155

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0353 AC: 136

ESP6500EA AF: 0.000727 AC: 6

ExAC AF: 0.00421 AC: 509

Asia WGS AF: 0.00318 AC: 12 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	19
DANN	Benign	0.75
DEOGEN2	Benign	0.0097	T
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.50	T
MetaRNN	Benign	0.0035	T
MutationTaster	Benign	1.0	D;D;D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.28
MVP		0.095
GERP RS		2.0
Varity_R		0.052
gMVP		0.14

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

Other links and lift over

dbSNP: rs73293424; hg19: chr14-73957816; COSMIC: COSV58374026;