18-74291736-C-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_148923.4(CYB5A):c.129+11G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0101 in 1,613,738 control chromosomes in the GnomAD database, including 310 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.011 (34 hom., cov: 32)
  • Exomes 𝑓: 0.010 (276 hom.)
• Consequence: CYB5A NM_148923.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.00600

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 18-74291736-C-A is Benign according to our data. Variant chr18-74291736-C-A is described in ClinVar as [Benign]. Clinvar id is 1601600.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0567 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYB5A	NM_148923.4	c.129+11G>T		intron_variant		ENST00000340533.9
CYB5A	NM_001190807.3	c.129+11G>T		intron_variant
CYB5A	NM_001914.4	c.129+11G>T		intron_variant
CYB5A	XM_011525835.3	c.129+11G>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYB5A	ENST00000340533.9	c.129+11G>T		intron_variant		1	NM_148923.4	P1
CYB5A	ENST00000494131.6	c.129+11G>T		intron_variant		1
CYB5A	ENST00000397914.4	c.129+11G>T		intron_variant		3
CYB5A	ENST00000583418.1	n.211+11G>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0114 AC: 1731 AN: 152234 Hom.: 34 Cov.: 32

Gnomad AFR AF: 0.00258

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0599

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0141

Gnomad FIN AF: 0.00536

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00816

Gnomad OTH AF: 0.00813

GnomAD3 exomes AF: 0.0195 AC: 4895 AN: 250732 Hom.: 185 AF XY: 0.0170 AC XY: 2310 AN XY: 135550

Gnomad AFR exome AF: 0.00191

Gnomad AMR exome AF: 0.0929

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.000544

Gnomad SAS exome AF: 0.0196

Gnomad FIN exome AF: 0.00528

Gnomad NFE exome AF: 0.00722

Gnomad OTH exome AF: 0.0158

GnomAD4 exome AF: 0.00996 AC: 14551 AN: 1461386 Hom.: 276 Cov.: 31 AF XY: 0.00974 AC XY: 7082 AN XY: 727048

Gnomad4 AFR exome AF: 0.00146

Gnomad4 AMR exome AF: 0.0865

Gnomad4 ASJ exome AF: 0.00149

Gnomad4 EAS exome AF: 0.000302

Gnomad4 SAS exome AF: 0.0187

Gnomad4 FIN exome AF: 0.00533

Gnomad4 NFE exome AF: 0.00731

Gnomad4 OTH exome AF: 0.00825

GnomAD4 genome AF: 0.0114 AC: 1731 AN: 152352 Hom.: 34 Cov.: 32 AF XY: 0.0129 AC XY: 958 AN XY: 74512

Gnomad4 AFR AF: 0.00257

Gnomad4 AMR AF: 0.0599

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.0137

Gnomad4 FIN AF: 0.00536

Gnomad4 NFE AF: 0.00816

Gnomad4 OTH AF: 0.00804

Alfa AF: 0.00862 Hom.: 1

Bravo AF: 0.0157

Asia WGS AF: 0.00924 AC: 32 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
Cadd	Benign	6.1
Dann	Benign	0.84
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs150530087; hg19: chr18-71958971;