NM_148923.4:c.-214C>T

Variant names:

• chr18-74292089-G-A
• rs77442034
• NM_148923.4:c.-214C>T

Variant summary

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

The NM_148923.4(CYB5A):​c.-214C>T variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.138 in 657,600 control chromosomes in the GnomAD database, including 7,224 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 0.12 (1392 hom., cov: 33)
  • Exomes 𝑓: 0.14 (5832 hom.)
• Consequence: CYB5A NM_148923.4 upstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.35
• Publications: 2 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

ENSG00000286529 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.184 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.-214C>T		upstream_gene	N/A	NP_683725.1
	CYB5A	NM_001190807.3		c.-214C>T		upstream_gene	N/A	NP_001177736.1
	CYB5A	NM_001914.4		c.-214C>T		upstream_gene	N/A	NP_001905.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYB5A	ENST00000340533.9	TSL:1 MANE Select	c.-214C>T		upstream_gene	N/A	ENSP00000341625.4
	CYB5A	ENST00000494131.6	TSL:1	c.-214C>T		upstream_gene	N/A	ENSP00000436461.2
	CYB5A	ENST00000886099.1		c.-214C>T		upstream_gene	N/A	ENSP00000556158.1

Frequencies

GnomAD3 genomes AF: 0.119 AC: 18072 AN: 152140 Hom.: 1388 Cov.: 33

Gnomad AFR AF: 0.0318

Gnomad AMI AF: 0.0428

Gnomad AMR AF: 0.189

Gnomad ASJ AF: 0.0922

Gnomad EAS AF: 0.0738

Gnomad SAS AF: 0.143

Gnomad FIN AF: 0.168

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.153

Gnomad OTH AF: 0.102

GnomAD4 exome AF: 0.144 AC: 72685 AN: 505342 Hom.: 5832 AF XY: 0.143 AC XY: 38423 AN XY: 267758

African (AFR) AF: 0.0283 AC: 407 AN: 14368

American (AMR) AF: 0.225 AC: 5732 AN: 25468

Ashkenazi Jewish (ASJ) AF: 0.0913 AC: 1369 AN: 14990

East Asian (EAS) AF: 0.0744 AC: 2259 AN: 30356

South Asian (SAS) AF: 0.141 AC: 7429 AN: 52842

European-Finnish (FIN) AF: 0.172 AC: 5054 AN: 29318

Middle Eastern (MID) AF: 0.0553 AC: 113 AN: 2044

European-Non Finnish (NFE) AF: 0.151 AC: 46716 AN: 308440

Other (OTH) AF: 0.131 AC: 3606 AN: 27516

GnomAD4 genome AF: 0.119 AC: 18089 AN: 152258 Hom.: 1392 Cov.: 33 AF XY: 0.120 AC XY: 8938 AN XY: 74440

African (AFR) AF: 0.0317 AC: 1317 AN: 41558

American (AMR) AF: 0.190 AC: 2901 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0922 AC: 320 AN: 3472

East Asian (EAS) AF: 0.0739 AC: 382 AN: 5166

South Asian (SAS) AF: 0.144 AC: 693 AN: 4828

European-Finnish (FIN) AF: 0.168 AC: 1785 AN: 10616

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.153 AC: 10422 AN: 67994

Other (OTH) AF: 0.101 AC: 214 AN: 2112

Alfa AF: 0.0568 Hom.: 66

Bravo AF: 0.115

Asia WGS AF: 0.107 AC: 373 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.0
DANN	Benign	0.85
PhyloP100		-1.3
PromoterAI		-0.29	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs77442034; hg19: chr18-71959324;