chr18-74263366-T-C

Position:

• chr18-74263366-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_148923.4(CYB5A):​c.241A>G​(p.Ile81Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,786 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: CYB5A NM_148923.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.07

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37559554).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYB5A	NM_148923.4	c.241A>G	p.Ile81Val	missense_variant	2/5	ENST00000340533.9	NP_683725.1
CYB5A	NM_001190807.3	c.241A>G	p.Ile81Val	missense_variant	2/4		NP_001177736.1
CYB5A	NM_001914.4	c.241A>G	p.Ile81Val	missense_variant	2/6		NP_001905.1
CYB5A	XM_011525835.3	c.241A>G	p.Ile81Val	missense_variant	2/4		XP_011524137.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYB5A	ENST00000340533.9	c.241A>G	p.Ile81Val	missense_variant	2/5	1	NM_148923.4	ENSP00000341625.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461786 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727184

Gnomad4 AFR exome AF: 0.00

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: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 03, 2022

The c.241A>G (p.I81V) alteration is located in exon 2 (coding exon 2) of the CYB5A gene. This alteration results from a A to G substitution at nucleotide position 241, causing the isoleucine (I) at amino acid position 81 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.014	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	21
DANN	Benign	0.95
DEOGEN2	Benign	0.35	T;.;.;.
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.084
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.81	T;T;T;T
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.38	T;T;T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	0.71	N;.;N;N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.76	N;.;N;N
REVEL	Benign	0.15
Sift	Benign	0.054	T;.;T;T
Sift4G	Benign	0.13	T;T;T;T
Polyphen		0.0080	B;.;B;.
Vest4		0.30
MutPred		0.61		Gain of ubiquitination at K77 (P = 0.0972);.;Gain of ubiquitination at K77 (P = 0.0972);Gain of ubiquitination at K77 (P = 0.0972);
MVP		0.83
MPC		0.070
ClinPred		0.56	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.59

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr18-71930601;