22-42693049-G-C

Position:

• chr22-42693049-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_017436.7(A4GALT):​c.903C>G​(p.Pro301=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.592 in 1,613,258 control chromosomes in the GnomAD database, including 286,528 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.65 (33422 hom., cov: 33)
  • Exomes 𝑓: 0.59 (253106 hom.)
• Consequence: A4GALT NM_017436.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.895

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 22-42693049-G-C is Benign according to our data. Variant chr22-42693049-G-C is described in ClinVar as [Benign]. Clinvar id is 1221433.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.895 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.823 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
A4GALT	NM_017436.7	c.903C>G	p.Pro301=	synonymous_variant	3/3	ENST00000642412.2	NP_059132.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
A4GALT	ENST00000642412.2	c.903C>G	p.Pro301=	synonymous_variant	3/3		NM_017436.7	ENSP00000494127	P1

Frequencies

GnomAD3 genomes AF: 0.652 AC: 99202 AN: 152068 Hom.: 33384 Cov.: 33

Gnomad AFR AF: 0.830

Gnomad AMI AF: 0.357

Gnomad AMR AF: 0.603

Gnomad ASJ AF: 0.561

Gnomad EAS AF: 0.694

Gnomad SAS AF: 0.594

Gnomad FIN AF: 0.607

Gnomad MID AF: 0.604

Gnomad NFE AF: 0.573

Gnomad OTH AF: 0.621

GnomAD3 exomes AF: 0.609 AC: 151838 AN: 249446 Hom.: 46827 AF XY: 0.602 AC XY: 81304 AN XY: 135096

Gnomad AFR exome AF: 0.829

Gnomad AMR exome AF: 0.618

Gnomad ASJ exome AF: 0.568

Gnomad EAS exome AF: 0.715

Gnomad SAS exome AF: 0.589

Gnomad FIN exome AF: 0.595

Gnomad NFE exome AF: 0.569

Gnomad OTH exome AF: 0.591

GnomAD4 exome AF: 0.586 AC: 856424 AN: 1461072 Hom.: 253106 Cov.: 80 AF XY: 0.584 AC XY: 424557 AN XY: 726856

Gnomad4 AFR exome AF: 0.836

Gnomad4 AMR exome AF: 0.615

Gnomad4 ASJ exome AF: 0.565

Gnomad4 EAS exome AF: 0.670

Gnomad4 SAS exome AF: 0.587

Gnomad4 FIN exome AF: 0.593

Gnomad4 NFE exome AF: 0.574

Gnomad4 OTH exome AF: 0.598

GnomAD4 genome AF: 0.652 AC: 99283 AN: 152186 Hom.: 33422 Cov.: 33 AF XY: 0.652 AC XY: 48504 AN XY: 74400

Gnomad4 AFR AF: 0.830

Gnomad4 AMR AF: 0.604

Gnomad4 ASJ AF: 0.561

Gnomad4 EAS AF: 0.694

Gnomad4 SAS AF: 0.593

Gnomad4 FIN AF: 0.607

Gnomad4 NFE AF: 0.573

Gnomad4 OTH AF: 0.615

Alfa AF: 0.550 Hom.: 6244

Bravo AF: 0.659

Asia WGS AF: 0.639 AC: 2222 AN: 3478

EpiCase AF: 0.559

EpiControl AF: 0.568

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 17, 2020	This variant is associated with the following publications: (PMID: 31374005) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

A4GALT-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 17, 2021

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.96
DANN	Benign	0.40

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

LitVar

Other links and lift over

dbSNP: rs6002904; hg19: chr22-43089055; COSMIC: COSV50744498; COSMIC: COSV50744498;