12-55996852-A-G

Variant names:

• chr12-55996852-A-G
• rs705702
• NM_002868.4:c.*4640A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001414458.1(RAB5B):​c.*4640A>G variant causes a downstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.24 in 151,990 control chromosomes in the GnomAD database, including 5,180 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.24 (5180 hom., cov: 31)
• Consequence: RAB5B NM_001414458.1 downstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.26
• Publications: 74 publications found

Genes affected

RAB5B (HGNC:9784): (RAB5B, member RAS oncogene family) Enables GDP binding activity; GTP-dependent protein binding activity; and GTPase activity. Involved in antigen processing and presentation and plasma membrane to endosome transport. Located in endosome and extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

SUOX (HGNC:11460): (sulfite oxidase) Sulfite oxidase is a homodimeric protein localized to the intermembrane space of mitochondria. Each subunit contains a heme domain and a molybdopterin-binding domain. The enzyme catalyzes the oxidation of sulfite to sulfate, the final reaction in the oxidative degradation of the sulfur amino acids cysteine and methionine. Sulfite oxidase deficiency results in neurological abnormalities which are often fatal at an early age. Alternative splicing results in multiple transcript variants encoding identical proteins. [provided by RefSeq, Jul 2008]

SUOX Gene-Disease associations (from GenCC):

• isolated sulfite oxidase deficiency

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.317 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001414458.1. 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
	RAB5B	NM_002868.4	MANE Select	c.*4640A>G		downstream_gene	N/A	NP_002859.1
	RAB5B	NM_001414458.1		c.*4640A>G		downstream_gene	N/A	NP_001401387.1
	RAB5B	NM_001252036.2		c.*4640A>G		downstream_gene	N/A	NP_001238965.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAB5B	ENST00000360299.10	TSL:1 MANE Select	c.*4640A>G		downstream_gene	N/A	ENSP00000353444.5
	SUOX	ENST00000886412.1		c.-670A>G		upstream_gene	N/A	ENSP00000556471.1
	SUOX	ENST00000886413.1		c.-1008A>G		upstream_gene	N/A	ENSP00000556472.1

Frequencies

GnomAD3 genomes AF: 0.241 AC: 36552 AN: 151872 Hom.: 5181 Cov.: 31

Gnomad AFR AF: 0.0884

Gnomad AMI AF: 0.512

Gnomad AMR AF: 0.237

Gnomad ASJ AF: 0.326

Gnomad EAS AF: 0.230

Gnomad SAS AF: 0.217

Gnomad FIN AF: 0.286

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.321

Gnomad OTH AF: 0.264

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.240 AC: 36553 AN: 151990 Hom.: 5180 Cov.: 31 AF XY: 0.237 AC XY: 17623 AN XY: 74288

African (AFR) AF: 0.0883 AC: 3659 AN: 41450

American (AMR) AF: 0.237 AC: 3619 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.326 AC: 1131 AN: 3472

East Asian (EAS) AF: 0.230 AC: 1187 AN: 5160

South Asian (SAS) AF: 0.218 AC: 1047 AN: 4808

European-Finnish (FIN) AF: 0.286 AC: 3022 AN: 10564

Middle Eastern (MID) AF: 0.235 AC: 69 AN: 294

European-Non Finnish (NFE) AF: 0.321 AC: 21801 AN: 67950

Other (OTH) AF: 0.261 AC: 551 AN: 2110

Alfa AF: 0.279 Hom.: 11400

Bravo AF: 0.234

Asia WGS AF: 0.179 AC: 625 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.6
DANN	Benign	0.47
PhyloP100		-2.3
PromoterAI		-0.0058	Neutral

Splicing

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

Other links and lift over

dbSNP: rs705702; hg19: chr12-56390636;