rs7238987

Variant names:

• chr18-74260915-C-T
• rs7238987
• NM_148923.4:c.288G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_148923.4(CYB5A):​c.288G>A​(p.Pro96Pro) 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. 3/3 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.65
• Publications: 26 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

ACMG classification

Our verdict: Benign. The variant received -21 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 VariationId is 1600597.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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 rank	MANE	Protein	UniProt
CYB5A	NM_148923.4	c.288G>A	p.Pro96Pro	splice_region_variant, synonymous_variant	Exon 3 of 5	ENST00000340533.9	NP_683725.1
CYB5A	NM_001914.4	c.288G>A	p.Pro96Pro	splice_region_variant, synonymous_variant	Exon 3 of 6		NP_001905.1
CYB5A	XM_011525835.3	c.288G>A	p.Pro96Pro	splice_region_variant, synonymous_variant	Exon 3 of 4		XP_011524137.1
CYB5A	NM_001190807.3	c.258+2434G>A		intron_variant	Intron 2 of 3		NP_001177736.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYB5A	ENST00000340533.9	c.288G>A	p.Pro96Pro	splice_region_variant, synonymous_variant	Exon 3 of 5	1	NM_148923.4	ENSP00000341625.4

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

GnomAD2 exomes AF: 0.157 AC: 39337 AN: 251228 AF XY: 0.152

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 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

African (AFR) AF: 0.138 AC: 4620 AN: 33396

American (AMR) AF: 0.240 AC: 10738 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.0975 AC: 2544 AN: 26092

East Asian (EAS) AF: 0.0824 AC: 3266 AN: 39646

South Asian (SAS) AF: 0.144 AC: 12429 AN: 86140

European-Finnish (FIN) AF: 0.173 AC: 9232 AN: 53312

Middle Eastern (MID) AF: 0.0755 AC: 434 AN: 5746

European-Non Finnish (NFE) AF: 0.163 AC: 180620 AN: 1107216

Other (OTH) AF: 0.148 AC: 8913 AN: 60220

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

African (AFR) AF: 0.149 AC: 6178 AN: 41506

American (AMR) AF: 0.212 AC: 3236 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.100 AC: 348 AN: 3470

East Asian (EAS) AF: 0.0859 AC: 445 AN: 5180

South Asian (SAS) AF: 0.147 AC: 707 AN: 4816

European-Finnish (FIN) AF: 0.166 AC: 1753 AN: 10542

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.152 AC: 10309 AN: 67978

Other (OTH) AF: 0.131 AC: 277 AN: 2110

Alfa AF: 0.149 Hom.: 7158

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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	22
DANN	Benign	0.60
PhyloP100		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=60/40	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7238987; hg19: chr18-71928150; COSMIC: COSV55022770;