Genetic Variant CYB5A:c.129+11G>T (chr18-74291736-C-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_148923.4(CYB5A):c.129+11G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0101 in 1,613,738 control chromosomes in the GnomAD database, including 310 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 34 hom., cov: 32)

Exomes 𝑓: 0.010 ( 276 hom. )

Consequence

CYB5A
NM_148923.4 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.00600

Publications

0 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.65).

BP6

Variant 18-74291736-C-A is Benign according to our data. Variant chr18-74291736-C-A is described in ClinVar as Benign. ClinVar VariationId is 1601600.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0567 is higher than 0.05.

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.129+11G>T	intron	N/A	NP_683725.1	P00167-1
CYB5A	NM_001190807.3		c.129+11G>T	intron	N/A	NP_001177736.1	P00167-3
CYB5A	NM_001914.4		c.129+11G>T	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.129+11G>T	intron	N/A	ENSP00000341625.4	P00167-1
CYB5A	ENST00000494131.6	TSL:1	c.129+11G>T	intron	N/A	ENSP00000436461.2	P00167-2
CYB5A	ENST00000886099.1		c.129+11G>T	intron	N/A	ENSP00000556158.1

Frequencies

GnomAD3 genomes

AF:

0.0114

AC:

1731

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00258

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0599

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.0141

Gnomad FIN

AF:

0.00536

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00816

Gnomad OTH

AF:

0.00813

GnomAD2 exomes

AF:

0.0195

AC:

4895

AN:

250732

AF XY:

0.0170

show subpopulations

Gnomad AFR exome

AF:

0.00191

Gnomad AMR exome

AF:

0.0929

Gnomad ASJ exome

AF:

0.00129

Gnomad EAS exome

AF:

0.000544

Gnomad FIN exome

AF:

0.00528

Gnomad NFE exome

AF:

0.00722

Gnomad OTH exome

AF:

0.0158

GnomAD4 exome

AF:

0.00996

AC:

14551

AN:

1461386

Hom.:

276

Cov.:

AF XY:

0.00974

AC XY:

7082

AN XY:

727048

show subpopulations

African (AFR)

AF:

0.00146

AC:

AN:

33458

American (AMR)

AF:

0.0865

AC:

3869

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00149

AC:

AN:

26120

East Asian (EAS)

AF:

0.000302

AC:

AN:

39684

South Asian (SAS)

AF:

0.0187

AC:

1609

AN:

86250

European-Finnish (FIN)

AF:

0.00533

AC:

284

AN:

53310

Middle Eastern (MID)

AF:

0.0115

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00731

AC:

8125

AN:

1111724

Other (OTH)

AF:

0.00825

AC:

498

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

922

1845

2767

3690

4612

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

362

724

1086

1448

1810

<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:

0.0114

AC:

1731

AN:

152352

Hom.:

Cov.:

AF XY:

0.0129

AC XY:

958

AN XY:

74512

show subpopulations

African (AFR)

AF:

0.00257

AC:

107

AN:

41582

American (AMR)

AF:

0.0599

AC:

917

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3470

East Asian (EAS)

AF:

0.000578

AC:

AN:

5186

South Asian (SAS)

AF:

0.0137

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00536

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00816

AC:

555

AN:

68032

Other (OTH)

AF:

0.00804

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

178

268

357

446

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:

0.00862

Hom.:

Bravo

AF:

0.0157

Asia WGS

AF:

0.00924

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

-0.65

CADD

Benign

6.1

(source)

DANN

Benign

0.84

PhyloP100

-0.0060

PromoterAI

-0.0086

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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