18-74291840-G-C

Position:

• chr18-74291840-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The ENST00000340533.9(CYB5A):​c.36C>G​(p.Tyr12Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Y12Y) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CYB5A ENST00000340533.9 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.826

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 Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.911 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYB5A	NM_148923.4	c.36C>G	p.Tyr12Ter	stop_gained	1/5	ENST00000340533.9	NP_683725.1
CYB5A	NM_001190807.3	c.36C>G	p.Tyr12Ter	stop_gained	1/4		NP_001177736.1
CYB5A	NM_001914.4	c.36C>G	p.Tyr12Ter	stop_gained	1/6		NP_001905.1
CYB5A	XM_011525835.3	c.36C>G	p.Tyr12Ter	stop_gained	1/4		XP_011524137.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYB5A	ENST00000340533.9	c.36C>G	p.Tyr12Ter	stop_gained	1/5	1	NM_148923.4	ENSP00000341625	P1
CYB5A	ENST00000494131.6	c.36C>G	p.Tyr12Ter	stop_gained	1/6	1		ENSP00000436461
CYB5A	ENST00000397914.4	c.36C>G	p.Tyr12Ter	stop_gained	1/4	3		ENSP00000381011
CYB5A	ENST00000583418.1	n.118C>G		non_coding_transcript_exon_variant	1/4	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	1.0	D
MutationTaster	Benign	1.0	A;A
Vest4		0.73
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6

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: rs1051236; hg19: chr18-71959075;