chr22-42718014-A-C

Variant names:

• chr22-42718014-A-C
• rs2143918
• NM_017436.7:c.-188+2783T>G

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+2783T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.424 in 152,098 control chromosomes in the GnomAD database, including 15,424 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 0.42 (15424 hom., cov: 33)
• Consequence: A4GALT NM_017436.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.05
• Publications: 9 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: STRONG Submitted by: G2P, 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=-0.81).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.802 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	A4GALT	NM_017436.7	MANE Select	c.-188+2783T>G		intron	N/A	NP_059132.1
	A4GALT	NM_001318038.3		c.-188+3151T>G		intron	N/A	NP_001304967.1
	A4GALT	NR_146459.3		n.*223T>G		downstream_gene	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	A4GALT	ENST00000642412.2	MANE Select	c.-188+2783T>G		intron	N/A	ENSP00000494127.1
	A4GALT	ENST00000381278.4	TSL:5	c.-104+2783T>G		intron	N/A	ENSP00000370678.3
	CYB5R3	ENST00000686129.1		c.-49+2783T>G		intron	N/A	ENSP00000508623.1

Frequencies

GnomAD3 genomes AF: 0.424 AC: 64436 AN: 151980 Hom.: 15429 Cov.: 33

Gnomad AFR AF: 0.205

Gnomad AMI AF: 0.416

Gnomad AMR AF: 0.463

Gnomad ASJ AF: 0.496

Gnomad EAS AF: 0.823

Gnomad SAS AF: 0.554

Gnomad FIN AF: 0.527

Gnomad MID AF: 0.525

Gnomad NFE AF: 0.488

Gnomad OTH AF: 0.457

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

GnomAD4 genome AF: 0.424 AC: 64443 AN: 152098 Hom.: 15424 Cov.: 33 AF XY: 0.431 AC XY: 32051 AN XY: 74358

African (AFR) AF: 0.205 AC: 8491 AN: 41484

American (AMR) AF: 0.463 AC: 7064 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.496 AC: 1720 AN: 3468

East Asian (EAS) AF: 0.822 AC: 4258 AN: 5178

South Asian (SAS) AF: 0.553 AC: 2671 AN: 4826

European-Finnish (FIN) AF: 0.527 AC: 5577 AN: 10580

Middle Eastern (MID) AF: 0.531 AC: 156 AN: 294

European-Non Finnish (NFE) AF: 0.488 AC: 33153 AN: 67984

Other (OTH) AF: 0.461 AC: 974 AN: 2112

Alfa AF: 0.448 Hom.: 3629

Bravo AF: 0.408

Asia WGS AF: 0.612 AC: 2128 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	8.6
DANN	Benign	0.72
PhyloP100		1.0

Splicing

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

Other links and lift over

dbSNP: rs2143918; hg19: chr22-43114020;