Genetic Variant CYB5A:c.-214C>A (chr18-74292089-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_148923.4(CYB5A):c.-214C>A variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000304 in 658,028 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000020 ( 0 hom. )

Consequence

CYB5A
NM_148923.4 upstream_gene

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.35

Publications

2 publications found

Variant links:

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

CYB5A links:

ENSG00000286529 (HGNC:):

ENSG00000286529 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
CYB5A	NM_148923.4	MANE Select	c.-214C>A	upstream_gene	N/A	NP_683725.1
CYB5A	NM_001190807.3		c.-214C>A	upstream_gene	N/A	NP_001177736.1
CYB5A	NM_001914.4		c.-214C>A	upstream_gene	N/A	NP_001905.1

Ensembl Transcripts

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

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000198

AC:

AN:

505860

Hom.:

AF XY:

0.00

AC XY:

AN XY:

268046

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

14368

American (AMR)

AF:

0.00

AC:

AN:

25510

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15000

East Asian (EAS)

AF:

0.00

AC:

AN:

30380

South Asian (SAS)

AF:

0.00

AC:

AN:

52860

European-Finnish (FIN)

AF:

0.00

AC:

AN:

29366

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2044

European-Non Finnish (NFE)

AF:

0.00000324

AC:

AN:

308792

Other (OTH)

AF:

0.00

AC:

AN:

27540

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152168

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41442

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.52

(source)

DANN

Benign

0.61

PhyloP100

-1.3

PromoterAI

-0.018

Neutral

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over