rs2276275

Positions:

• chr18-74253620-G-A
• chr18-74253620-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_148923.4(CYB5A):​c.369C>T​(p.Val123=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00384 in 1,613,372 control chromosomes in the GnomAD database, including 167 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 0.0064 (15 hom., cov: 33)
  • Exomes 𝑓: 0.0036 (152 hom.)
• Consequence: CYB5A NM_148923.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.75

Genes affected

CYB5A (HGNC:2570): (cytochrome b5 type A) The protein encoded by this gene is a membrane-bound cytochrome that reduces ferric hemoglobin (methemoglobin) to ferrous hemoglobin, which is required for stearyl-CoA-desaturase activity. Defects in this gene are a cause of type IV hereditary methemoglobinemia. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2010]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP7: Synonymous conserved (PhyloP=-1.75 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0554 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYB5A	NM_148923.4	c.369C>T	p.Val123=	synonymous_variant	5/5	ENST00000340533.9	NP_683725.1
CYB5A	NM_001190807.3	c.339C>T	p.Val113=	synonymous_variant	4/4		NP_001177736.1
CYB5A	NM_001914.4	c.*96C>T		3_prime_UTR_variant	6/6		NP_001905.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYB5A	ENST00000340533.9	c.369C>T	p.Val123=	synonymous_variant	5/5	1	NM_148923.4	ENSP00000341625	P1

Frequencies

GnomAD3 genomes AF: 0.00643 AC: 979 AN: 152180 Hom.: 14 Cov.: 33

Gnomad AFR AF: 0.00203

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0381

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0537

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00716

GnomAD3 exomes AF: 0.0126 AC: 3149 AN: 250906 Hom.: 103 AF XY: 0.00996 AC XY: 1350 AN XY: 135602

Gnomad AFR exome AF: 0.00222

Gnomad AMR exome AF: 0.0611

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.0498

Gnomad SAS exome AF: 0.000556

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.00881

GnomAD4 exome AF: 0.00357 AC: 5220 AN: 1461074 Hom.: 152 Cov.: 29 AF XY: 0.00323 AC XY: 2351 AN XY: 726872

Gnomad4 AFR exome AF: 0.00152

Gnomad4 AMR exome AF: 0.0572

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.0571

Gnomad4 SAS exome AF: 0.000673

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.0000774

Gnomad4 OTH exome AF: 0.00325

GnomAD4 genome AF: 0.00643 AC: 980 AN: 152298 Hom.: 15 Cov.: 33 AF XY: 0.00768 AC XY: 572 AN XY: 74460

Gnomad4 AFR AF: 0.00202

Gnomad4 AMR AF: 0.0382

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.0536

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00709

Alfa AF: 0.00505 Hom.: 3

Bravo AF: 0.00994

Asia WGS AF: 0.0150 AC: 53 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000296

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.16
DANN	Benign	0.48

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: rs2276275; hg19: chr18-71920855; COSMIC: COSV55023138;