chr17-44251230-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_000342.4(SLC4A1):c.2584G>A(p.Val862Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00508 in 1,614,054 control chromosomes in the GnomAD database, including 350 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V862V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.027 ( 193 hom., cov: 32)

Exomes 𝑓: 0.0028 ( 157 hom. )

Consequence

SLC4A1
NM_000342.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.860

Publications

11 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 -18 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 4 uncertain in NM_000342.4

BP4

Computational evidence support a benign effect (MetaRNN=0.0018474758).

BP6

Variant 17-44251230-C-T is Benign according to our data. Variant chr17-44251230-C-T is described in ClinVar as Benign. ClinVar VariationId is 255911.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0921 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.2584G>A	p.Val862Ile	missense	Exon 19 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.2584G>A	p.Val862Ile	missense	Exon 19 of 20	ENSP00000262418.6	P02730-1
	SLC4A1	ENST00000399246.3	TSL:5	c.1486G>A	p.Val496Ile	missense	Exon 14 of 15	ENSP00000382190.3	A0A0A0MS98

Frequencies

GnomAD3 genomes

AF:

0.0273

AC:

4153

AN:

152176

Hom.:

192

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0945

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0120

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.0206

GnomAD2 exomes

AF:

0.00725

AC:

1817

AN:

250562

AF XY:

0.00542

show subpopulations

Gnomad AFR exome

AF:

0.0988

Gnomad AMR exome

AF:

0.00498

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000159

Gnomad OTH exome

AF:

0.00343

GnomAD4 exome

AF:

0.00276

AC:

4039

AN:

1461760

Hom.:

157

Cov.:

AF XY:

0.00230

AC XY:

1669

AN XY:

727176

show subpopulations

African (AFR)

AF:

0.0975

AC:

3263

AN:

33480

American (AMR)

AF:

0.00575

AC:

257

AN:

44680

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.000441

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53390

Middle Eastern (MID)

AF:

0.00382

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0000674

AC:

AN:

1111984

Other (OTH)

AF:

0.00634

AC:

383

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

257

513

770

1026

1283

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

204

306

408

510

<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:

0.0274

AC:

4166

AN:

152294

Hom.:

193

Cov.:

AF XY:

0.0264

AC XY:

1968

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.0945

AC:

3927

AN:

41542

American (AMR)

AF:

0.0119

AC:

182

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000162

AC:

AN:

68016

Other (OTH)

AF:

0.0204

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

195

390

584

779

974

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

176

220

<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:

0.0270

Hom.:

2480

Bravo

AF:

0.0324

ESP6500AA

AF:

0.0953

AC:

420

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00910

AC:

1105

Asia WGS

AF:

0.00491

AC:

AN:

3478

EpiCase

AF:

0.000436

EpiControl

AF:

0.000237

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Autosomal dominant distal renal tubular acidosis (1)

Hemolytic anemia (1)

Hereditary spherocytosis type 4 (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.66

CADD

Benign

3.8

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.16

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.81

MetaRNN

Benign

0.0018

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.46

PhyloP100

-0.86

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.22

REVEL

Benign

0.036

Sift

Benign

0.53

Sift4G

Benign

0.38

Polyphen

0.0070

Vest4

0.080

MVP

0.22

MPC

0.29

ClinPred

0.0044

GERP RS

-3.9

Varity_R

0.045

gMVP

0.44

Mutation Taster

=97/3

polymorphism (auto)

(source)

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

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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