chr22-42693708-GGAA-G

Variant names:

• chr22-42693708-GGAA-G
• rs387906279
• NM_017436.7:c.241_243delTTC

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PM4_Supporting

The NM_017436.7(A4GALT):​c.241_243delTTC​(p.Phe81del) variant causes a conservative inframe deletion change. The variant allele was found at a frequency of 0.0000548 in 1,405,400 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Affects (no stars).

• Frequency:
  • Genomes: 𝑓 0.000049 (0 hom., cov: 26)
  • Exomes 𝑓: 0.000055 (0 hom.)
• Consequence: A4GALT NM_017436.7 conservative_inframe_deletion
• Clinical Significance: Affects no assertion criteria provided O:1
• Conservation: PhyloP100: 6.30
• Publications: 5 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_017436.7. Strenght limited to Supporting due to length of the change: 1aa.

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.241_243delTTC	p.Phe81del	conservative_inframe_deletion	Exon 3 of 3	NP_059132.1
	A4GALT	NM_001318038.3		c.241_243delTTC	p.Phe81del	conservative_inframe_deletion	Exon 3 of 3	NP_001304967.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	A4GALT	ENST00000642412.2	MANE Select	c.241_243delTTC	p.Phe81del	conservative_inframe_deletion	Exon 3 of 3	ENSP00000494127.1
	A4GALT	ENST00000249005.3	TSL:1	c.241_243delTTC	p.Phe81del	conservative_inframe_deletion	Exon 2 of 2	ENSP00000249005.2
	A4GALT	ENST00000401850.5	TSL:1	c.241_243delTTC	p.Phe81del	conservative_inframe_deletion	Exon 2 of 2	ENSP00000384794.1

Frequencies

GnomAD3 genomes AF: 0.0000488 AC: 7 AN: 143482 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.0000253

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000207

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000458

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000399 AC: 10 AN: 250810 AF XY: 0.0000368

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000530

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000555 AC: 70 AN: 1261918 Hom.: 0 AF XY: 0.0000543 AC XY: 34 AN XY: 625976

African (AFR) AF: 0.00 AC: 0 AN: 27620

American (AMR) AF: 0.000104 AC: 4 AN: 38602

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18834

East Asian (EAS) AF: 0.00 AC: 0 AN: 23268

South Asian (SAS) AF: 0.0000237 AC: 2 AN: 84300

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34630

Middle Eastern (MID) AF: 0.000212 AC: 1 AN: 4722

European-Non Finnish (NFE) AF: 0.0000580 AC: 57 AN: 982910

Other (OTH) AF: 0.000128 AC: 6 AN: 47032

GnomAD4 genome AF: 0.0000488 AC: 7 AN: 143482 Hom.: 0 Cov.: 26 AF XY: 0.0000430 AC XY: 3 AN XY: 69754

African (AFR) AF: 0.0000253 AC: 1 AN: 39488

American (AMR) AF: 0.000207 AC: 3 AN: 14504

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3364

East Asian (EAS) AF: 0.00 AC: 0 AN: 4314

South Asian (SAS) AF: 0.00 AC: 0 AN: 3812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 308

European-Non Finnish (NFE) AF: 0.0000458 AC: 3 AN: 65460

Other (OTH) AF: 0.00 AC: 0 AN: 1964

Alfa AF: 0.00 Hom.: 0

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Affects

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	-	p phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.3
Mutation Taster		=60/40	polymorphism

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: rs387906279; hg19: chr22-43089714;