Genetic Variant CYB5A:p.Trp27Gly (chr18-74291797-A-C) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_148923.4(CYB5A):c.79T>G(p.Trp27Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000155 in 1,613,756 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

CYB5A
NM_148923.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.08

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.98

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYB5A	NM_148923.4 link	c.79T>G	p.Trp27Gly	missense_variant	Exon 1 of 5	ENST00000340533.9	NP_683725.1	P00167-1A0A384ME44
CYB5A	NM_001190807.3 link	c.79T>G	p.Trp27Gly	missense_variant	Exon 1 of 4		NP_001177736.1	P00167-3
CYB5A	NM_001914.4 link	c.79T>G	p.Trp27Gly	missense_variant	Exon 1 of 6		NP_001905.1	P00167-2
CYB5A	XM_011525835.3 link	c.79T>G	p.Trp27Gly	missense_variant	Exon 1 of 4		XP_011524137.1	P00167-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CYB5A	ENST00000340533.9 link	c.79T>G	p.Trp27Gly	missense_variant	Exon 1 of 5	1	NM_148923.4	ENSP00000341625.4	P00167-1
CYB5A	ENST00000494131.6 link	c.79T>G	p.Trp27Gly	missense_variant	Exon 1 of 6	1		ENSP00000436461.2	P00167-2
CYB5A	ENST00000397914.4 link	c.79T>G	p.Trp27Gly	missense_variant	Exon 1 of 4	3		ENSP00000381011.4	P00167-3
CYB5A	ENST00000583418.1 link	n.161T>G		non_coding_transcript_exon_variant	Exon 1 of 4	2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251320

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135832

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000157

AC:

AN:

1461584

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727114

show subpopulations

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:

0.0000207

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000772

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.79T>G (p.W27G) alteration is located in exon 1 (coding exon 1) of the CYB5A gene. This alteration results from a T to G substitution at nucleotide position 79, causing the tryptophan (W) at amino acid position 27 to be replaced by a glycine (G). 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

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Pathogenic

0.21

CADD

Pathogenic

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.93

D;.;.

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.81

T;T;T

M_CAP

Pathogenic

0.50

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Pathogenic

0.85

MutationAssessor

Pathogenic

4.5

H;H;H

PrimateAI

Uncertain

0.71

PROVEAN

Pathogenic

-12

D;D;D

REVEL

Pathogenic

0.75

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.91

MutPred

0.89

Gain of disorder (P = 0.0117);Gain of disorder (P = 0.0117);Gain of disorder (P = 0.0117);

MVP

1.0

MPC

0.55

ClinPred

1.0

GERP RS

4.2

Varity_R

0.97

gMVP

0.95

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over