18-74291863-A-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_148923.4(CYB5A):c.13T>G(p.Ser5Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000528 in 1,612,202 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0030 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00027 (3 hom.)
• Consequence: CYB5A NM_148923.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -0.722

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030369163).
• BP6: Variant 18-74291863-A-C is Benign according to our data. Variant chr18-74291863-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 252595.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=1}.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYB5A	NM_148923.4	c.13T>G	p.Ser5Ala	missense_variant	1/5	ENST00000340533.9
CYB5A	NM_001190807.3	c.13T>G	p.Ser5Ala	missense_variant	1/4
CYB5A	NM_001914.4	c.13T>G	p.Ser5Ala	missense_variant	1/6
CYB5A	XM_011525835.3	c.13T>G	p.Ser5Ala	missense_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYB5A	ENST00000340533.9	c.13T>G	p.Ser5Ala	missense_variant	1/5	1	NM_148923.4	P1
CYB5A	ENST00000494131.6	c.13T>G	p.Ser5Ala	missense_variant	1/6	1
CYB5A	ENST00000397914.4	c.13T>G	p.Ser5Ala	missense_variant	1/4	3
CYB5A	ENST00000583418.1	n.95T>G		non_coding_transcript_exon_variant	1/4	2

Frequencies

GnomAD3 genomes AF: 0.00303 AC: 459 AN: 151282 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00985

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00243

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00321

Gnomad NFE AF: 0.0000884

Gnomad OTH AF: 0.00484

GnomAD3 exomes AF: 0.000749 AC: 188 AN: 251016 Hom.: 1 AF XY: 0.000501 AC XY: 68 AN XY: 135740

Gnomad AFR exome AF: 0.00923

Gnomad AMR exome AF: 0.000896

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: 0.0000264

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000269 AC: 393 AN: 1460802 Hom.: 3 Cov.: 32 AF XY: 0.000215 AC XY: 156 AN XY: 726772

Gnomad4 AFR exome AF: 0.00864

Gnomad4 AMR exome AF: 0.000984

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: 0.0000108

Gnomad4 OTH exome AF: 0.000762

GnomAD4 genome AF: 0.00303 AC: 459 AN: 151400 Hom.: 4 Cov.: 32 AF XY: 0.00300 AC XY: 222 AN XY: 73922

Gnomad4 AFR AF: 0.00983

Gnomad4 AMR AF: 0.00243

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000884

Gnomad4 OTH AF: 0.00478

Alfa AF: 0.00136 Hom.: 0

Bravo AF: 0.00366

ESP6500AA AF: 0.0104 AC: 46

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000939 AC: 114

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 16, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Aug 24, 2015	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 30, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	15
Dann	Benign	0.94
DEOGEN2	Benign	0.18	T;.;.
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.97
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.34	T;T;T
MetaRNN	Benign	0.0030	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.77	N;N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.55	N;N;N
REVEL	Benign	0.078
Sift	Benign	0.27	T;T;T
Sift4G	Benign	0.35	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.085
MVP		0.73
MPC		0.063
ClinPred		0.0025	T
GERP RS		-0.34
Varity_R		0.14
gMVP		0.25

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: rs75160992; hg19: chr18-71959098;