18-74291851-C-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM2 BP4_Strong BP6_Very_Strong

The NM_148923.4(CYB5A):c.25G>T(p.Val9Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000725 in 1,613,434 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000068 (0 hom.)
• Consequence: CYB5A NM_148923.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.70

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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.010828614).
• BP6: Variant 18-74291851-C-A is Benign according to our data. Variant chr18-74291851-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 727030.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYB5A	NM_148923.4	c.25G>T	p.Val9Leu	missense_variant	1/5	ENST00000340533.9
CYB5A	NM_001190807.3	c.25G>T	p.Val9Leu	missense_variant	1/4
CYB5A	NM_001914.4	c.25G>T	p.Val9Leu	missense_variant	1/6
CYB5A	XM_011525835.3	c.25G>T	p.Val9Leu	missense_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYB5A	ENST00000340533.9	c.25G>T	p.Val9Leu	missense_variant	1/5	1	NM_148923.4	P1
CYB5A	ENST00000494131.6	c.25G>T	p.Val9Leu	missense_variant	1/6	1
CYB5A	ENST00000397914.4	c.25G>T	p.Val9Leu	missense_variant	1/4	3
CYB5A	ENST00000583418.1	n.107G>T		non_coding_transcript_exon_variant	1/4	2

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00328

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000342 AC: 86 AN: 251204 Hom.: 0 AF XY: 0.000280 AC XY: 38 AN XY: 135798

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00429

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000678 AC: 99 AN: 1461146 Hom.: 0 Cov.: 32 AF XY: 0.0000702 AC XY: 51 AN XY: 726946

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00179

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000248

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152288 Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6 AN XY: 74462

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00329

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000159

ExAC AF: 0.000329 AC: 40

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Oct 23, 2018

- -

CYB5A-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 08, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.20
Cadd	Uncertain	26
Dann	Uncertain	0.99
DEOGEN2	Benign	0.23	T;.;.
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.18
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.76	T;T;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.011	T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	-0.29	N;N;N
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.7	N;N;N
REVEL	Benign	0.16
Sift	Uncertain	0.0030	D;T;D
Sift4G	Benign	0.19	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.56
MutPred		0.30		Loss of methylation at K10 (P = 0.0448);Loss of methylation at K10 (P = 0.0448);Loss of methylation at K10 (P = 0.0448);
MVP		0.76
MPC		0.081
ClinPred		0.15	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.37
gMVP		0.38

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: rs201644903; hg19: chr18-71959086;