chr18-74253620-G-A

Variant names:

• chr18-74253620-G-A
• rs2276275
• NM_148923.4:c.369C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_148923.4(CYB5A):​c.369C>T​(p.Val123Val) 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
• Publications: 5 publications found

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]

CYB5A Gene-Disease associations (from GenCC):

• methemoglobinemia type 4

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• 46,XY disorder of sex development due to isolated 17,20-lyase deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_148923.4. 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
	CYB5A	NM_148923.4	MANE Select	c.369C>T	p.Val123Val	synonymous	Exon 5 of 5	NP_683725.1
	CYB5A	NM_001190807.3		c.339C>T	p.Val113Val	synonymous	Exon 4 of 4	NP_001177736.1
	CYB5A	NM_001914.4		c.*96C>T		3_prime_UTR	Exon 6 of 6	NP_001905.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYB5A	ENST00000340533.9	TSL:1 MANE Select	c.369C>T	p.Val123Val	synonymous	Exon 5 of 5	ENSP00000341625.4
	CYB5A	ENST00000494131.6	TSL:1	c.*96C>T		3_prime_UTR	Exon 6 of 6	ENSP00000436461.2
	CYB5A	ENST00000580678.5	TSL:1	n.848C>T		non_coding_transcript_exon	Exon 3 of 3

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

GnomAD2 exomes AF: 0.0126 AC: 3149 AN: 250906 AF XY: 0.00996

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 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

African (AFR) AF: 0.00152 AC: 51 AN: 33454

American (AMR) AF: 0.0572 AC: 2556 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26112

East Asian (EAS) AF: 0.0571 AC: 2266 AN: 39672

South Asian (SAS) AF: 0.000673 AC: 58 AN: 86208

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53304

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5758

European-Non Finnish (NFE) AF: 0.0000774 AC: 86 AN: 1111534

Other (OTH) AF: 0.00325 AC: 196 AN: 60346

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

African (AFR) AF: 0.00202 AC: 84 AN: 41566

American (AMR) AF: 0.0382 AC: 584 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.0536 AC: 277 AN: 5166

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68024

Other (OTH) AF: 0.00709 AC: 15 AN: 2116

Alfa AF: 0.00467 Hom.: 4

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.16
DANN	Benign	0.48
PhyloP100		-1.7
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

Other links and lift over

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