17-44249354-AT-A

Position:

• chr17-44249354-AT-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_000342.4(SLC4A1):​c.*1103del variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0295 in 313,780 control chromosomes in the GnomAD database, including 881 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.057 (834 hom., cov: 28)
  • Exomes 𝑓: 0.0037 (47 hom.)
• Consequence: SLC4A1 NM_000342.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:3
• Conservation: PhyloP100: -0.0490

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP6: Variant 17-44249354-AT-A is Benign according to our data. Variant chr17-44249354-AT-A is described in ClinVar as [Likely_benign]. Clinvar id is 323488.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.195 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC4A1	NM_000342.4	c.*1103del		3_prime_UTR_variant	20/20	ENST00000262418.12	NP_000333.1
SLC4A1	XM_005257593.6	c.*1103del		3_prime_UTR_variant	18/18		XP_005257650.1
SLC4A1	XM_011525129.3	c.*1103del		3_prime_UTR_variant	19/19		XP_011523431.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC4A1	ENST00000262418.12	c.*1103del		3_prime_UTR_variant	20/20	1	NM_000342.4	ENSP00000262418	P1
SLC4A1	ENST00000399246.3	c.*1103del		3_prime_UTR_variant	15/15	5		ENSP00000382190

Frequencies

GnomAD3 genomes AF: 0.0567 AC: 8626 AN: 152144 Hom.: 827 Cov.: 28

Gnomad AFR AF: 0.198

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0177

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000970

Gnomad OTH AF: 0.0454

GnomAD4 exome AF: 0.00373 AC: 603 AN: 161518 Hom.: 47 Cov.: 0 AF XY: 0.00334 AC XY: 304 AN XY: 91110

Gnomad4 AFR exome AF: 0.168

Gnomad4 AMR exome AF: 0.00981

Gnomad4 ASJ exome AF: 0.000585

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000762

Gnomad4 FIN exome AF: 0.000131

Gnomad4 NFE exome AF: 0.000602

Gnomad4 OTH exome AF: 0.0105

GnomAD4 genome AF: 0.0569 AC: 8663 AN: 152262 Hom.: 834 Cov.: 28 AF XY: 0.0544 AC XY: 4052 AN XY: 74460

Gnomad4 AFR AF: 0.198

Gnomad4 AMR AF: 0.0178

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000970

Gnomad4 OTH AF: 0.0449

Alfa AF: 0.00138 Hom.: 1

Bravo AF: 0.0641

Asia WGS AF: 0.0160 AC: 55 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

Distal Renal Tubular Acidosis, Dominant Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Spherocytosis, Dominant Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Hemolytic anemia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

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: rs111655803; hg19: chr17-42326722;