rs1051236

Variant names:

• chr18-74291840-G-A
• rs1051236
• NM_148923.4:c.36C>T

Your query was ambiguous. Multiple possible variants found:

• chr18-74291840-G-A
• chr18-74291840-G-C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_148923.4(CYB5A):​c.36C>T​(p.Tyr12Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.155 in 1,613,590 control chromosomes in the GnomAD database, including 21,090 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1391 hom., cov: 32)
  • Exomes 𝑓: 0.16 (19699 hom.)
• Consequence: CYB5A NM_148923.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.826
• Publications: 10 publications found

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

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 18-74291840-G-A is Benign according to our data. Variant chr18-74291840-G-A is described in ClinVar as Benign. ClinVar VariationId is 1599637.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.184 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYB5A	NM_148923.4	MANE Select	c.36C>T	p.Tyr12Tyr	synonymous	Exon 1 of 5	NP_683725.1	P00167-1
	CYB5A	NM_001190807.3		c.36C>T	p.Tyr12Tyr	synonymous	Exon 1 of 4	NP_001177736.1	P00167-3
	CYB5A	NM_001914.4		c.36C>T	p.Tyr12Tyr	synonymous	Exon 1 of 6	NP_001905.1	P00167-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYB5A	ENST00000340533.9	TSL:1 MANE Select	c.36C>T	p.Tyr12Tyr	synonymous	Exon 1 of 5	ENSP00000341625.4	P00167-1
	CYB5A	ENST00000494131.6	TSL:1	c.36C>T	p.Tyr12Tyr	synonymous	Exon 1 of 6	ENSP00000436461.2	P00167-2
	CYB5A	ENST00000886099.1		c.36C>T	p.Tyr12Tyr	synonymous	Exon 1 of 6	ENSP00000556158.1

Frequencies

GnomAD3 genomes AF: 0.119 AC: 18055 AN: 152026 Hom.: 1387 Cov.: 32

Gnomad AFR AF: 0.0318

Gnomad AMI AF: 0.0428

Gnomad AMR AF: 0.189

Gnomad ASJ AF: 0.0920

Gnomad EAS AF: 0.0741

Gnomad SAS AF: 0.142

Gnomad FIN AF: 0.168

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.153

Gnomad OTH AF: 0.101

GnomAD2 exomes AF: 0.148 AC: 37075 AN: 251354 AF XY: 0.146

Gnomad AFR exome AF: 0.0294

Gnomad AMR exome AF: 0.235

Gnomad ASJ exome AF: 0.0939

Gnomad EAS exome AF: 0.0689

Gnomad FIN exome AF: 0.171

Gnomad NFE exome AF: 0.154

Gnomad OTH exome AF: 0.138

GnomAD4 exome AF: 0.159 AC: 232308 AN: 1461446 Hom.: 19699 Cov.: 33 AF XY: 0.157 AC XY: 114457 AN XY: 727056

African (AFR) AF: 0.0230 AC: 769 AN: 33462

American (AMR) AF: 0.233 AC: 10421 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0905 AC: 2365 AN: 26128

East Asian (EAS) AF: 0.0751 AC: 2981 AN: 39692

South Asian (SAS) AF: 0.142 AC: 12214 AN: 86250

European-Finnish (FIN) AF: 0.175 AC: 9294 AN: 53214

Middle Eastern (MID) AF: 0.0612 AC: 353 AN: 5764

European-Non Finnish (NFE) AF: 0.167 AC: 185491 AN: 1111856

Other (OTH) AF: 0.139 AC: 8420 AN: 60364

GnomAD4 genome AF: 0.119 AC: 18072 AN: 152144 Hom.: 1391 Cov.: 32 AF XY: 0.120 AC XY: 8924 AN XY: 74348

African (AFR) AF: 0.0317 AC: 1317 AN: 41530

American (AMR) AF: 0.190 AC: 2899 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0920 AC: 319 AN: 3468

East Asian (EAS) AF: 0.0742 AC: 383 AN: 5160

South Asian (SAS) AF: 0.143 AC: 686 AN: 4804

European-Finnish (FIN) AF: 0.168 AC: 1781 AN: 10584

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.153 AC: 10420 AN: 67992

Other (OTH) AF: 0.101 AC: 212 AN: 2108

Alfa AF: 0.117 Hom.: 758

Bravo AF: 0.115

Asia WGS AF: 0.107 AC: 373 AN: 3478

EpiCase AF: 0.137

EpiControl AF: 0.138

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	13
DANN	Benign	0.93
PhyloP100		0.83
PromoterAI		-0.061	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1051236; hg19: chr18-71959075; COSMIC: COSV55021885; COSMIC: COSV55021885;