Genetic Variant CYB5R4:p.Thr58Ala (chr6-83864271-A-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_016230.4(CYB5R4):c.172A>G(p.Thr58Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,240 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CYB5R4
NM_016230.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.84

Variant links:

Genes affected

CYB5R4 (HGNC:20147): (cytochrome b5 reductase 4) NCB5OR is a flavohemoprotein that contains functional domains found in both cytochrome b5 (CYB5A; MIM 613218) and CYB5 reductase (CYB5R3; MIM 613213) (Zhu et al., 1999 [PubMed 10611283]).[supplied by OMIM, Jan 2010]

CYB5R4 links:

RIPPLY2-CYB5R4 (HGNC:):

RIPPLY2-CYB5R4 links:

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ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
CYB5R4	NM_016230.4 link	c.172A>G	p.Thr58Ala	missense_variant	Exon 2 of 16	ENST00000369681.10	NP_057314.2	Q7L1T6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYB5R4	ENST00000369681.10 link	c.172A>G	p.Thr58Ala	missense_variant	Exon 2 of 16	1	NM_016230.4	ENSP00000358695.3		Q7L1T6
CYB5R4	ENST00000369679.4 link	c.70A>G	p.Thr24Ala	missense_variant	Exon 2 of 5	3		ENSP00000358693.4		A0A0A0MRM6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000797

AC:

AN:

251068

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135716

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000580

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461240

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726936

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

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.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.172A>G (p.T58A) alteration is located in exon 2 (coding exon 2) of the CYB5R4 gene. This alteration results from a A to G substitution at nucleotide position 172, causing the threonine (T) at amino acid position 58 to be replaced by an alanine (A). 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

0.21

BayesDel_addAF

Uncertain

0.034

BayesDel_noAF

Uncertain

-0.010

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.57

D;T

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.92

D;D

M_CAP

Uncertain

0.11

MetaRNN

Uncertain

0.74

D;D

MetaSVM

Uncertain

0.30

MutationAssessor

Pathogenic

2.9

M;.

PrimateAI

Uncertain

0.70

PROVEAN

Uncertain

-3.0

D;D

REVEL

Pathogenic

0.72

Sift

Uncertain

0.0070

D;D

Sift4G

Benign

0.064

T;T

Polyphen

0.62

P;.

Vest4

0.70

MutPred

0.71

Loss of methylation at K63 (P = 0.0642);.;

MVP

0.94

MPC

0.55

ClinPred

0.96

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.41

gMVP

0.78

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