17-44248849-GTTTTTTTTTTTTTTTT-GTTTTTTTTTTTTTTTTTTT

Variant names:

• chr17-44248849-G-GTTT
• rs57466226
• NM_000342.4:c.*1606_*1608dupAAA

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_000342.4(SLC4A1):​c.*1606_*1608dupAAA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2852 hom., cov: 0)
  • Exomes 𝑓: 0.0011 (4 hom.)
  • Failed GnomAD Quality Control
• Consequence: SLC4A1 NM_000342.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: -0.697
• Publications: 1 publications found

Genes affected

SLC4A1 (HGNC:11027): (solute carrier family 4 member 1 (Diego blood group)) The protein encoded by this gene is part of the anion exchanger (AE) family and is expressed in the erythrocyte plasma membrane, where it functions as a chloride/bicarbonate exchanger involved in carbon dioxide transport from tissues to lungs. The protein comprises two domains that are structurally and functionally distinct. The N-terminal 40kDa domain is located in the cytoplasm and acts as an attachment site for the red cell skeleton by binding ankyrin. The glycosylated C-terminal membrane-associated domain contains 12-14 membrane spanning segments and carries out the stilbene disulphonate-sensitive exchange transport of anions. The cytoplasmic tail at the extreme C-terminus of the membrane domain binds carbonic anhydrase II. The encoded protein associates with the red cell membrane protein glycophorin A and this association promotes the correct folding and translocation of the exchanger. This protein is predominantly dimeric but forms tetramers in the presence of ankyrin. Many mutations in this gene are known in man, and these mutations can lead to two types of disease: destabilization of red cell membrane leading to hereditary spherocytosis, and defective kidney acid secretion leading to distal renal tubular acidosis. Other mutations that do not give rise to disease result in novel blood group antigens, which form the Diego blood group system. Southeast Asian ovalocytosis (SAO, Melanesian ovalocytosis) results from the heterozygous presence of a deletion in the encoded protein and is common in areas where Plasmodium falciparum malaria is endemic. One null mutation in this gene is known, resulting in very severe anemia and nephrocalcinosis. [provided by RefSeq, Jul 2008]

SLC4A1 Gene-Disease associations (from GenCC):

• autosomal dominant distal renal tubular acidosis

  Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
• cryohydrocytosis

  Inheritance: AD, Unknown Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia
• hereditary spherocytosis type 4

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• southeast Asian ovalocytosis

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• renal tubular acidosis, distal, 4, with hemolytic anemia

  Inheritance: AR, AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Orphanet
• dehydrated hereditary stomatocytosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary spherocytosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High Homozygotes in GnomAdExome4 at 4 AD,AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000342.4. 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
	SLC4A1	NM_000342.4	MANE Select	c.*1606_*1608dupAAA		3_prime_UTR	Exon 20 of 20	NP_000333.1	P02730-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC4A1	ENST00000262418.12	TSL:1 MANE Select	c.*1606_*1608dupAAA		3_prime_UTR	Exon 20 of 20	ENSP00000262418.6	P02730-1
	SLC4A1	ENST00000399246.3	TSL:5	c.*1606_*1608dupAAA		3_prime_UTR	Exon 15 of 15	ENSP00000382190.3	A0A0A0MS98

Frequencies

GnomAD3 genomes AF: 0.170 AC: 10322 AN: 60762 Hom.: 2852 Cov.: 0

Gnomad AFR AF: 0.216

Gnomad AMI AF: 0.0809

Gnomad AMR AF: 0.139

Gnomad ASJ AF: 0.284

Gnomad EAS AF: 0.548

Gnomad SAS AF: 0.0695

Gnomad FIN AF: 0.0183

Gnomad MID AF: 0.0238

Gnomad NFE AF: 0.149

Gnomad OTH AF: 0.161

GnomAD4 exome AF: 0.00109 AC: 12 AN: 11020 Hom.: 4 Cov.: 0 AF XY: 0.000501 AC XY: 3 AN XY: 5990

African (AFR) AF: 0.00 AC: 0 AN: 42

American (AMR) AF: 0.00 AC: 0 AN: 658

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 164

East Asian (EAS) AF: 0.00 AC: 0 AN: 54

South Asian (SAS) AF: 0.000566 AC: 1 AN: 1766

European-Finnish (FIN) AF: 0.00345 AC: 2 AN: 580

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 32

European-Non Finnish (NFE) AF: 0.00125 AC: 9 AN: 7194

Other (OTH) AF: 0.00 AC: 0 AN: 530

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.170 AC: 10322 AN: 60768 Hom.: 2852 Cov.: 0 AF XY: 0.164 AC XY: 4434 AN XY: 26970

African (AFR) AF: 0.216 AC: 2762 AN: 12778

American (AMR) AF: 0.139 AC: 593 AN: 4278

Ashkenazi Jewish (ASJ) AF: 0.284 AC: 555 AN: 1952

East Asian (EAS) AF: 0.547 AC: 811 AN: 1482

South Asian (SAS) AF: 0.0698 AC: 117 AN: 1676

European-Finnish (FIN) AF: 0.0183 AC: 34 AN: 1858

Middle Eastern (MID) AF: 0.0256 AC: 2 AN: 78

European-Non Finnish (NFE) AF: 0.149 AC: 5282 AN: 35362

Other (OTH) AF: 0.161 AC: 122 AN: 760

Alfa AF: 0.0285 Hom.: 73

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Distal Renal Tubular Acidosis, Dominant (1)
-	1	-	Hemolytic anemia (1)
-	1	-	not provided (1)
-	1	-	Spherocytosis, Dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.70
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs57466226; hg19: chr17-42326217;