rs7238987

chr18-74260915-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_148923.4(CYB5A):c.288G>A(p.Pro96=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.159 in 1,608,572 control chromosomes in the GnomAD database, including 21,414 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.15 (1863 hom., cov: 33)
  • Exomes 𝑓: 0.16 (19551 hom.)
• Consequence: CYB5A NM_148923.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.2584
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.65

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 18-74260915-C-T is Benign according to our data. Variant chr18-74260915-C-T is described in ClinVar as [Benign]. Clinvar id is 1600597.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.65 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.206 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYB5A	NM_148923.4	c.288G>A	p.Pro96=	splice_region_variant, synonymous_variant	3/5	ENST00000340533.9
CYB5A	NM_001914.4	c.288G>A	p.Pro96=	splice_region_variant, synonymous_variant	3/6
CYB5A	XM_011525835.3	c.288G>A	p.Pro96=	splice_region_variant, synonymous_variant	3/4
CYB5A	NM_001190807.3	c.258+2434G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYB5A	ENST00000340533.9	c.288G>A	p.Pro96=	splice_region_variant, synonymous_variant	3/5	1	NM_148923.4	P1

Frequencies

GnomAD3 genomes AF: 0.153 AC: 23288 AN: 151978 Hom.: 1856 Cov.: 33

Gnomad AFR AF: 0.149

Gnomad AMI AF: 0.0428

Gnomad AMR AF: 0.211

Gnomad ASJ AF: 0.100

Gnomad EAS AF: 0.0859

Gnomad SAS AF: 0.146

Gnomad FIN AF: 0.166

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.152

Gnomad OTH AF: 0.132

GnomAD3 exomes AF: 0.157 AC: 39337 AN: 251228 Hom.: 3464 AF XY: 0.152 AC XY: 20690 AN XY: 135778

Gnomad AFR exome AF: 0.149

Gnomad AMR exome AF: 0.241

Gnomad ASJ exome AF: 0.103

Gnomad EAS exome AF: 0.0794

Gnomad SAS exome AF: 0.139

Gnomad FIN exome AF: 0.171

Gnomad NFE exome AF: 0.152

Gnomad OTH exome AF: 0.147

GnomAD4 exome AF: 0.160 AC: 232796 AN: 1456476 Hom.: 19551 Cov.: 29 AF XY: 0.158 AC XY: 114687 AN XY: 724832

Gnomad4 AFR exome AF: 0.138

Gnomad4 AMR exome AF: 0.240

Gnomad4 ASJ exome AF: 0.0975

Gnomad4 EAS exome AF: 0.0824

Gnomad4 SAS exome AF: 0.144

Gnomad4 FIN exome AF: 0.173

Gnomad4 NFE exome AF: 0.163

Gnomad4 OTH exome AF: 0.148

GnomAD4 genome AF: 0.153 AC: 23311 AN: 152096 Hom.: 1863 Cov.: 33 AF XY: 0.154 AC XY: 11414 AN XY: 74340

Gnomad4 AFR AF: 0.149

Gnomad4 AMR AF: 0.212

Gnomad4 ASJ AF: 0.100

Gnomad4 EAS AF: 0.0859

Gnomad4 SAS AF: 0.147

Gnomad4 FIN AF: 0.166

Gnomad4 NFE AF: 0.152

Gnomad4 OTH AF: 0.131

Alfa AF: 0.146 Hom.: 3626

Bravo AF: 0.156

Asia WGS AF: 0.120 AC: 419 AN: 3478

EpiCase AF: 0.136

EpiControl AF: 0.137

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 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
Cadd	Benign	22
Dann	Benign	0.60
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.26
dbscSNV1_RF	Benign	0.49
SpliceAI score (max)		0.040		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: rs7238987; hg19: chr18-71928150; COSMIC: COSV55022770;