rs8136914

Variant names:

• chr22-42716668-A-G
• rs8136914
• NM_017436.7:c.-188+4129T>C

Your query was ambiguous. Multiple possible variants found:

• chr22-42716668-A-G
• chr22-42716668-A-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_017436.7(A4GALT):​c.-188+4129T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.209 in 152,108 control chromosomes in the GnomAD database, including 4,140 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.21 (4140 hom., cov: 32)
• Consequence: A4GALT NM_017436.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.688
• Publications: 7 publications found

Genes affected

A4GALT (HGNC:18149): (alpha 1,4-galactosyltransferase (P1PK blood group)) The protein encoded by this gene catalyzes the transfer of galactose to lactosylceramide to form globotriaosylceramide, which has been identified as the P(k) antigen of the P blood group system. This protein, a type II membrane protein found in the Golgi, is also required for the synthesis of the bacterial verotoxins receptor. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Dec 2015]

CYB5R3 (HGNC:2873): (cytochrome b5 reductase 3) This gene encodes cytochrome b5 reductase, which includes a membrane-bound form in somatic cells (anchored in the endoplasmic reticulum, mitochondrial and other membranes) and a soluble form in erythrocytes. The membrane-bound form exists mainly on the cytoplasmic side of the endoplasmic reticulum and functions in desaturation and elongation of fatty acids, in cholesterol biosynthesis, and in drug metabolism. The erythrocyte form is located in a soluble fraction of circulating erythrocytes and is involved in methemoglobin reduction. The membrane-bound form has both membrane-binding and catalytic domains, while the soluble form has only the catalytic domain. Alternate splicing results in multiple transcript variants. Mutations in this gene cause methemoglobinemias. [provided by RefSeq, Jan 2010]

CYB5R3 Gene-Disease associations (from GenCC):

• methemoglobinemia

  Inheritance: AR Classification: DEFINITIVE Submitted by: Illumina
• methemoglobinemia due to deficiency of methemoglobin reductase

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• hereditary methemoglobinemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.352 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017436.7. 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
	A4GALT	NM_017436.7	MANE Select	c.-188+4129T>C		intron	N/A	NP_059132.1	A0A0S2Z5J1
	A4GALT	NM_001318038.3		c.-188+4497T>C		intron	N/A	NP_001304967.1	A0A0S2Z5J1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	A4GALT	ENST00000642412.2	MANE Select	c.-188+4129T>C		intron	N/A	ENSP00000494127.1	Q9NPC4
	A4GALT	ENST00000381278.4	TSL:5	c.-104+4129T>C		intron	N/A	ENSP00000370678.3	Q9NPC4
	A4GALT	ENST00000868257.1		c.-188+4497T>C		intron	N/A	ENSP00000538316.1

Frequencies

GnomAD3 genomes AF: 0.209 AC: 31714 AN: 151990 Hom.: 4137 Cov.: 32

Gnomad AFR AF: 0.0546

Gnomad AMI AF: 0.340

Gnomad AMR AF: 0.241

Gnomad ASJ AF: 0.290

Gnomad EAS AF: 0.214

Gnomad SAS AF: 0.366

Gnomad FIN AF: 0.231

Gnomad MID AF: 0.287

Gnomad NFE AF: 0.273

Gnomad OTH AF: 0.237

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.209 AC: 31723 AN: 152108 Hom.: 4140 Cov.: 32 AF XY: 0.210 AC XY: 15585 AN XY: 74358

African (AFR) AF: 0.0545 AC: 2264 AN: 41532

American (AMR) AF: 0.241 AC: 3676 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.290 AC: 1004 AN: 3468

East Asian (EAS) AF: 0.214 AC: 1108 AN: 5166

South Asian (SAS) AF: 0.366 AC: 1761 AN: 4810

European-Finnish (FIN) AF: 0.231 AC: 2447 AN: 10584

Middle Eastern (MID) AF: 0.295 AC: 86 AN: 292

European-Non Finnish (NFE) AF: 0.273 AC: 18557 AN: 67986

Other (OTH) AF: 0.242 AC: 511 AN: 2108

Alfa AF: 0.268 Hom.: 4596

Bravo AF: 0.198

Asia WGS AF: 0.286 AC: 998 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.69
DANN	Benign	0.76
PhyloP100		-0.69

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs8136914; hg19: chr22-43112674;