rs778598915

Positions:

• chr22-42693910-G-A
• chr22-42693910-G-C
• chr22-42693910-G-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_017436.7(A4GALT):​c.42C>T​(p.Gly14=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000206 in 1,453,932 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: A4GALT NM_017436.7 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter P:1 B:1
• Conservation: PhyloP100: -2.19

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 Likely_benign. Variant got -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 22-42693910-G-A is Benign according to our data. Variant chr22-42693910-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 39436.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-2.19 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
A4GALT	NM_017436.7	c.42C>T	p.Gly14=	synonymous_variant	3/3	ENST00000642412.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
A4GALT	ENST00000642412.2	c.42C>T	p.Gly14=	synonymous_variant	3/3		NM_017436.7	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000216 AC: 5 AN: 231460 Hom.: 0 AF XY: 0.0000316 AC XY: 4 AN XY: 126546

Gnomad AFR exome AF: 0.0000729

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000696

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000194

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000206 AC: 30 AN: 1453932 Hom.: 0 Cov.: 35 AF XY: 0.0000208 AC XY: 15 AN XY: 722538

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000236

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000207

Gnomad4 OTH exome AF: 0.0000499

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Pathogenic:1 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Infantile cortical hyperostosis Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 13, 2011

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jun 22, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.8
DANN	Benign	0.67

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: rs778598915; hg19: chr22-43089916;