18-74263490-G-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_148923.4(CYB5A):c.130-13C>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00698 in 1,613,948 control chromosomes in the GnomAD database, including 104 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0058 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0071 (97 hom.)
• Consequence: CYB5A NM_148923.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.40

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 18-74263490-G-T is Benign according to our data. Variant chr18-74263490-G-T is described in ClinVar as [Benign]. Clinvar id is 1600582.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYB5A	NM_148923.4	c.130-13C>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000340533.9
CYB5A	NM_001190807.3	c.130-13C>A		splice_polypyrimidine_tract_variant, intron_variant
CYB5A	NM_001914.4	c.130-13C>A		splice_polypyrimidine_tract_variant, intron_variant
CYB5A	XM_011525835.3	c.130-13C>A		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYB5A	ENST00000340533.9	c.130-13C>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_148923.4	P1

Frequencies

GnomAD3 genomes AF: 0.00582 AC: 886 AN: 152152 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.0362

Gnomad AMR AF: 0.00629

Gnomad ASJ AF: 0.0401

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0101

Gnomad FIN AF: 0.000755

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00703

Gnomad OTH AF: 0.0144

GnomAD3 exomes AF: 0.00731 AC: 1836 AN: 251160 Hom.: 28 AF XY: 0.00797 AC XY: 1082 AN XY: 135804

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.00422

Gnomad ASJ exome AF: 0.0416

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0135

Gnomad FIN exome AF: 0.00143

Gnomad NFE exome AF: 0.00659

Gnomad OTH exome AF: 0.00995

GnomAD4 exome AF: 0.00710 AC: 10379 AN: 1461678 Hom.: 97 Cov.: 31 AF XY: 0.00744 AC XY: 5410 AN XY: 727152

Gnomad4 AFR exome AF: 0.00155

Gnomad4 AMR exome AF: 0.00458

Gnomad4 ASJ exome AF: 0.0444

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0141

Gnomad4 FIN exome AF: 0.00135

Gnomad4 NFE exome AF: 0.00629

Gnomad4 OTH exome AF: 0.00980

GnomAD4 genome AF: 0.00583 AC: 888 AN: 152270 Hom.: 7 Cov.: 32 AF XY: 0.00536 AC XY: 399 AN XY: 74444

Gnomad4 AFR AF: 0.00123

Gnomad4 AMR AF: 0.00628

Gnomad4 ASJ AF: 0.0401

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0104

Gnomad4 FIN AF: 0.000755

Gnomad4 NFE AF: 0.00704

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.0102 Hom.: 4

Bravo AF: 0.00637

Asia WGS AF: 0.00231 AC: 8 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	-0.86
Cadd	Benign	1.1
Dann	Benign	0.50
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs146344037; hg19: chr18-71930725;