rs5036

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000342.4(SLC4A1):c.166A>G(p.Lys56Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0323 in 1,614,042 control chromosomes in the GnomAD database, including 1,705 homozygotes. In-silico tool predicts a benign outcome for this variant. 18/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K56R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.049 ( 342 hom., cov: 32)

Exomes 𝑓: 0.031 ( 1363 hom. )

Consequence

SLC4A1
NM_000342.4 missense, splice_region

Scores

Splicing: ADA: 0.00005328

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:11

Conservation

PhyloP100: 0.337

Publications

52 publications found

Variant links:

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

SLC4A1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002771765).

BP6

Variant 17-44261577-T-C is Benign according to our data. Variant chr17-44261577-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 17752.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0958 is higher than 0.05.

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.166A>G	p.Lys56Glu	missense splice_region	Exon 4 of 20	NP_000333.1	P02730-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC4A1	ENST00000262418.12	TSL:1 MANE Select	c.166A>G	p.Lys56Glu	missense splice_region	Exon 4 of 20	ENSP00000262418.6	P02730-1
SLC4A1	ENST00000399246.3	TSL:5	c.166A>G	p.Lys56Glu	missense splice_region	Exon 4 of 15	ENSP00000382190.3	A0A0A0MS98
SLC4A1	ENST00000471005.5	TSL:3	n.100A>G		splice_region non_coding_transcript_exon	Exon 2 of 4

Frequencies

GnomAD3 genomes

AF:

0.0493

AC:

7503

AN:

152094

Hom.:

342

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0985

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0643

Gnomad ASJ

AF:

0.0389

Gnomad EAS

AF:

0.0855

Gnomad SAS

AF:

0.0296

Gnomad FIN

AF:

0.00527

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0231

Gnomad OTH

AF:

0.0416

GnomAD2 exomes

AF:

0.0446

AC:

11216

AN:

251446

AF XY:

0.0392

show subpopulations

Gnomad AFR exome

AF:

0.101

Gnomad AMR exome

AF:

0.124

Gnomad ASJ exome

AF:

0.0406

Gnomad EAS exome

AF:

0.0702

Gnomad FIN exome

AF:

0.00628

Gnomad NFE exome

AF:

0.0210

Gnomad OTH exome

AF:

0.0360

GnomAD4 exome

AF:

0.0306

AC:

44670

AN:

1461830

Hom.:

1363

Cov.:

AF XY:

0.0300

AC XY:

21796

AN XY:

727224

show subpopulations

African (AFR)

AF:

0.102

AC:

3412

AN:

33480

American (AMR)

AF:

0.117

AC:

5221

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0393

AC:

1028

AN:

26136

East Asian (EAS)

AF:

0.125

AC:

4949

AN:

39698

South Asian (SAS)

AF:

0.0290

AC:

2499

AN:

86258

European-Finnish (FIN)

AF:

0.00689

AC:

368

AN:

53416

Middle Eastern (MID)

AF:

0.0342

AC:

197

AN:

5768

European-Non Finnish (NFE)

AF:

0.0223

AC:

24771

AN:

1111954

Other (OTH)

AF:

0.0368

AC:

2225

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

2664

5328

7992

10656

13320

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1110

2220

3330

4440

5550

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0494

AC:

7514

AN:

152212

Hom.:

342

Cov.:

AF XY:

0.0483

AC XY:

3591

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.0984

AC:

4084

AN:

41518

American (AMR)

AF:

0.0643

AC:

982

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.0389

AC:

135

AN:

3470

East Asian (EAS)

AF:

0.0857

AC:

443

AN:

5172

South Asian (SAS)

AF:

0.0301

AC:

145

AN:

4824

European-Finnish (FIN)

AF:

0.00527

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0231

AC:

1570

AN:

68010

Other (OTH)

AF:

0.0421

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

357

714

1071

1428

1785

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

156

234

312

390

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0347

Hom.:

481

Bravo

AF:

0.0582

TwinsUK

AF:

0.0175

AC:

ALSPAC

AF:

0.0218

AC:

ESP6500AA

AF:

0.102

AC:

450

ESP6500EA

AF:

0.0228

AC:

196

ExAC

AF:

0.0424

AC:

5152

Asia WGS

AF:

0.0730

AC:

255

AN:

3478

EpiCase

AF:

0.0225

EpiControl

AF:

0.0228

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (3)

Hereditary spherocytosis type 4 (2)

Autosomal dominant distal renal tubular acidosis (1)

BAND 3 MEMPHIS (1)

Hemolytic anemia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.58

CADD

Benign

5.3

(source)

DANN

Benign

0.17

DEOGEN2

Benign

0.12

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.013

LIST_S2

Benign

0.064

MetaRNN

Benign

0.0028

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-2.0

PhyloP100

0.34

PrimateAI

Benign

0.26

PROVEAN

Benign

2.1

REVEL

Benign

0.079

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.072

MPC

0.49

ClinPred

0.0000096

GERP RS

3.6

Varity_R

0.26

gMVP

0.18

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000053

dbscSNV1_RF

Benign

0.0040

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over