rs1803366

Positions:

• chr18-74263452-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_148923.4(CYB5A):​c.155G>A​(p.Arg52Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,862 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CYB5A NM_148923.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.92

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• 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.155G>A	p.Arg52Lys	missense_variant	2/5	ENST00000340533.9	NP_683725.1
CYB5A	NM_001190807.3	c.155G>A	p.Arg52Lys	missense_variant	2/4		NP_001177736.1
CYB5A	NM_001914.4	c.155G>A	p.Arg52Lys	missense_variant	2/6		NP_001905.1
CYB5A	XM_011525835.3	c.155G>A	p.Arg52Lys	missense_variant	2/4		XP_011524137.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYB5A	ENST00000340533.9	c.155G>A	p.Arg52Lys	missense_variant	2/5	1	NM_148923.4	ENSP00000341625.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461862 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727234

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.048	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	T;.;.
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Benign	0.042	D
MetaRNN	Uncertain	0.48	T;T;T
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	-0.49	N;N;N
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.4	N;N;N
REVEL	Uncertain	0.31
Sift	Uncertain	0.021	D;D;D
Sift4G	Uncertain	0.017	D;T;D
Polyphen		0.33	B;P;.
Vest4		0.60
MutPred		0.53		Gain of ubiquitination at R52 (P = 0.0131);Gain of ubiquitination at R52 (P = 0.0131);Gain of ubiquitination at R52 (P = 0.0131);
MVP		0.90
MPC		0.43
ClinPred		0.94	D
GERP RS		5.8
Varity_R		0.40
gMVP		0.73

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: rs1803366; hg19: chr18-71930687;