Genetic Variant NM_148923.4:c.130-13C>A (chr18-74263490-G-T) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_148923.4(CYB5A):c.130-13C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00698 in 1,613,948 control chromosomes in the GnomAD database, including 104 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0058 ( 7 hom., cov: 32)

Exomes 𝑓: 0.0071 ( 97 hom. )

Consequence

CYB5A
NM_148923.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -2.40

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

methemoglobinemia type 4
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
46,XY disorder of sex development due to isolated 17,20-lyase deficiency
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CYB5A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 18-74263490-G-T is Benign according to our data. Variant chr18-74263490-G-T is described in ClinVar as Benign. ClinVar VariationId is 1600582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_148923.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CYB5A	NM_148923.4	MANE Select	c.130-13C>A	intron	N/A	NP_683725.1	P00167-1
CYB5A	NM_001190807.3		c.130-13C>A	intron	N/A	NP_001177736.1	P00167-3
CYB5A	NM_001914.4		c.130-13C>A	intron	N/A	NP_001905.1	P00167-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CYB5A	ENST00000340533.9	TSL:1 MANE Select	c.130-13C>A	intron	N/A	ENSP00000341625.4	P00167-1
CYB5A	ENST00000494131.6	TSL:1	c.130-13C>A	intron	N/A	ENSP00000436461.2	P00167-2
CYB5A	ENST00000886099.1		c.130-13C>A	intron	N/A	ENSP00000556158.1

Frequencies

GnomAD3 genomes

AF:

0.00582

AC:

886

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00123

Gnomad AMI

AF:

0.0362

Gnomad AMR

AF:

0.00629

Gnomad ASJ

AF:

0.0401

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0101

Gnomad FIN

AF:

0.000755

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00703

Gnomad OTH

AF:

0.0144

GnomAD2 exomes

AF:

0.00731

AC:

1836

AN:

251160

AF XY:

0.00797

show subpopulations

Gnomad AFR exome

AF:

0.00105

Gnomad AMR exome

AF:

0.00422

Gnomad ASJ exome

AF:

0.0416

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00143

Gnomad NFE exome

AF:

0.00659

Gnomad OTH exome

AF:

0.00995

GnomAD4 exome

AF:

0.00710

AC:

10379

AN:

1461678

Hom.:

Cov.:

AF XY:

0.00744

AC XY:

5410

AN XY:

727152

show subpopulations

African (AFR)

AF:

0.00155

AC:

AN:

33476

American (AMR)

AF:

0.00458

AC:

205

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0444

AC:

1161

AN:

26132

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.0141

AC:

1214

AN:

86256

European-Finnish (FIN)

AF:

0.00135

AC:

AN:

53396

Middle Eastern (MID)

AF:

0.0153

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00629

AC:

6994

AN:

1111840

Other (OTH)

AF:

0.00980

AC:

592

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

508

1016

1525

2033

2541

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

282

564

846

1128

1410

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00583

AC:

888

AN:

152270

Hom.:

Cov.:

AF XY:

0.00536

AC XY:

399

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.00123

AC:

AN:

41560

American (AMR)

AF:

0.00628

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0401

AC:

139

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.0104

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000755

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00704

AC:

479

AN:

68026

Other (OTH)

AF:

0.0142

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

146

194

243

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0102

Hom.:

Bravo

AF:

0.00637

Asia WGS

AF:

0.00231

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

1.1

(source)

DANN

Benign

0.50

PhyloP100

-2.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over