chr17-44248737-C-T

Variant names:

• chr17-44248737-C-T
• rs62078947
• NM_000342.4:c.*1721G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000342.4(SLC4A1):​c.*1721G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0218 in 158,346 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (49 hom., cov: 31)
  • Exomes 𝑓: 0.026 (3 hom.)
• Consequence: SLC4A1 NM_000342.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.956
• Publications: 4 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 17-44248737-C-T is Benign according to our data. Variant chr17-44248737-C-T is described in ClinVar as Benign. ClinVar VariationId is 323475.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0216 (3287/151958) while in subpopulation NFE AF = 0.033 (2245/67978). AF 95% confidence interval is 0.0319. There are 49 homozygotes in GnomAd4. There are 1579 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 49 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.*1721G>A		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.*1721G>A		3_prime_UTR	Exon 20 of 20	ENSP00000262418.6	P02730-1
	SLC4A1	ENST00000399246.3	TSL:5	c.*1721G>A		3_prime_UTR	Exon 15 of 15	ENSP00000382190.3	A0A0A0MS98

Frequencies

GnomAD3 genomes AF: 0.0217 AC: 3288 AN: 151848 Hom.: 48 Cov.: 31

Gnomad AFR AF: 0.00579

Gnomad AMI AF: 0.0866

Gnomad AMR AF: 0.0200

Gnomad ASJ AF: 0.0135

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0102

Gnomad FIN AF: 0.0245

Gnomad MID AF: 0.0160

Gnomad NFE AF: 0.0330

Gnomad OTH AF: 0.0294

GnomAD4 exome AF: 0.0258 AC: 165 AN: 6388 Hom.: 3 Cov.: 0 AF XY: 0.0247 AC XY: 86 AN XY: 3476

African (AFR) AF: 0.00 AC: 0 AN: 32

American (AMR) AF: 0.00980 AC: 6 AN: 612

Ashkenazi Jewish (ASJ) AF: 0.0417 AC: 3 AN: 72

East Asian (EAS) AF: 0.00 AC: 0 AN: 48

South Asian (SAS) AF: 0.00466 AC: 3 AN: 644

European-Finnish (FIN) AF: 0.0303 AC: 6 AN: 198

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 22

European-Non Finnish (NFE) AF: 0.0320 AC: 142 AN: 4436

Other (OTH) AF: 0.0154 AC: 5 AN: 324

GnomAD4 genome AF: 0.0216 AC: 3287 AN: 151958 Hom.: 49 Cov.: 31 AF XY: 0.0213 AC XY: 1579 AN XY: 74244

African (AFR) AF: 0.00577 AC: 239 AN: 41430

American (AMR) AF: 0.0200 AC: 305 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.0135 AC: 47 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.00997 AC: 48 AN: 4816

European-Finnish (FIN) AF: 0.0245 AC: 258 AN: 10542

Middle Eastern (MID) AF: 0.0172 AC: 5 AN: 290

European-Non Finnish (NFE) AF: 0.0330 AC: 2245 AN: 67978

Other (OTH) AF: 0.0286 AC: 60 AN: 2100

Alfa AF: 0.0272 Hom.: 47

Bravo AF: 0.0213

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Autosomal dominant distal renal tubular acidosis (1)
-	-	1	Hemolytic anemia (1)
-	-	1	Hereditary spherocytosis type 4 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.48
DANN	Benign	0.64
PhyloP100		-0.96
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	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: rs62078947; hg19: chr17-42326105;