rs137123

Variant names:

• chr22-42619486-G-T
• rs137123
• NM_000398.7:c.*287C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000398.7(CYB5R3):​c.*287C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.258 in 481,864 control chromosomes in the GnomAD database, including 24,620 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (13022 hom., cov: 33)
  • Exomes 𝑓: 0.22 (11598 hom.)
• Consequence: CYB5R3 NM_000398.7 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.70

Genes affected

CYB5R3 (HGNC:2873): (cytochrome b5 reductase 3) This gene encodes cytochrome b5 reductase, which includes a membrane-bound form in somatic cells (anchored in the endoplasmic reticulum, mitochondrial and other membranes) and a soluble form in erythrocytes. The membrane-bound form exists mainly on the cytoplasmic side of the endoplasmic reticulum and functions in desaturation and elongation of fatty acids, in cholesterol biosynthesis, and in drug metabolism. The erythrocyte form is located in a soluble fraction of circulating erythrocytes and is involved in methemoglobin reduction. The membrane-bound form has both membrane-binding and catalytic domains, while the soluble form has only the catalytic domain. Alternate splicing results in multiple transcript variants. Mutations in this gene cause methemoglobinemias. [provided by RefSeq, Jan 2010]

ENSG00000289517 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 22-42619486-G-T is Benign according to our data. Variant chr22-42619486-G-T is described in ClinVar as [Benign]. Clinvar id is 1271243.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.681 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYB5R3	NM_000398.7	c.*287C>A		3_prime_UTR_variant	Exon 9 of 9	ENST00000352397.10	NP_000389.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYB5R3	ENST00000352397	c.*287C>A		3_prime_UTR_variant	Exon 9 of 9	1	NM_000398.7	ENSP00000338461.6
ENSG00000289517	ENST00000617178.5	n.*206+81C>A		intron_variant	Intron 4 of 13	1		ENSP00000482500.2

Frequencies

GnomAD3 genomes AF: 0.339 AC: 51417 AN: 151850 Hom.: 13002 Cov.: 33

Gnomad AFR AF: 0.688

Gnomad AMI AF: 0.136

Gnomad AMR AF: 0.219

Gnomad ASJ AF: 0.158

Gnomad EAS AF: 0.686

Gnomad SAS AF: 0.273

Gnomad FIN AF: 0.171

Gnomad MID AF: 0.291

Gnomad NFE AF: 0.171

Gnomad OTH AF: 0.301

GnomAD4 exome AF: 0.221 AC: 72790 AN: 329896 Hom.: 11598 Cov.: 0 AF XY: 0.220 AC XY: 37997 AN XY: 172384

Gnomad4 AFR exome AF: 0.678 AC: 6347 AN: 9362

Gnomad4 AMR exome AF: 0.178 AC: 2621 AN: 14694

Gnomad4 ASJ exome AF: 0.139 AC: 1444 AN: 10390

Gnomad4 EAS exome AF: 0.640 AC: 13190 AN: 20612

Gnomad4 SAS exome AF: 0.236 AC: 8892 AN: 37722

Gnomad4 FIN exome AF: 0.171 AC: 3532 AN: 20698

Gnomad4 NFE exome AF: 0.163 AC: 31929 AN: 196010

Gnomad4 Remaining exome AF: 0.236 AC: 4465 AN: 18956

GnomAD4 genome AF: 0.339 AC: 51491 AN: 151968 Hom.: 13022 Cov.: 33 AF XY: 0.336 AC XY: 24964 AN XY: 74302

Gnomad4 AFR AF: 0.688 AC: 0.688165 AN: 0.688165

Gnomad4 AMR AF: 0.219 AC: 0.218775 AN: 0.218775

Gnomad4 ASJ AF: 0.158 AC: 0.157925 AN: 0.157925

Gnomad4 EAS AF: 0.686 AC: 0.685848 AN: 0.685848

Gnomad4 SAS AF: 0.273 AC: 0.27335 AN: 0.27335

Gnomad4 FIN AF: 0.171 AC: 0.171197 AN: 0.171197

Gnomad4 NFE AF: 0.171 AC: 0.170958 AN: 0.170958

Gnomad4 OTH AF: 0.299 AC: 0.299052 AN: 0.299052

Alfa AF: 0.262 Hom.: 1000

Bravo AF: 0.360

Asia WGS AF: 0.438 AC: 1519 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.043
DANN	Benign	0.59
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs137123; hg19: chr22-43015492; COSMIC: COSV52810176; COSMIC: COSV52810176;