Genetic Variant NM_133478.3:c.3268G>A (chr2-74222931-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_133478.3(SLC4A5):c.3268G>A(p.Val1090Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0282 in 1,611,980 control chromosomes in the GnomAD database, including 779 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.023 ( 54 hom., cov: 32)

Exomes 𝑓: 0.029 ( 725 hom. )

Consequence

SLC4A5
NM_133478.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.601

Publications

11 publications found

Variant links:

Genes affected

SLC4A5 (HGNC:18168): (solute carrier family 4 member 5) This gene encodes a member of the sodium bicarbonate cotransporter (NBC) family, part of the bicarbonate transporter superfamily. Sodium bicarbonate cotransporters are involved in intracellular pH regulation and electroneural or electrogenic sodium bicarbonate transport. This protein is thought to be an integral membrane protein. Multiple transcript variants encoding different isoforms have been found for this gene, but the biological validity of some variants has not been determined. [provided by RefSeq, Jul 2008]

SLC4A5 links:

ENSG00000264324 (HGNC:):

ENSG00000264324 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0024946332).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0228 (3469/152108) while in subpopulation NFE AF = 0.0318 (2161/68018). AF 95% confidence interval is 0.0307. There are 54 homozygotes in GnomAd4. There are 1725 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 54 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_133478.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC4A5	NM_133478.3	MANE Select	c.3268G>A	p.Val1090Ile	missense	Exon 29 of 31	NP_597812.1	Q9BY07-3
SLC4A5	NM_021196.3		c.3316G>A	p.Val1106Ile	missense	Exon 25 of 26	NP_067019.3	Q9BY07-1
SLC4A5	NM_001386136.1		c.2920G>A	p.Val974Ile	missense	Exon 23 of 25	NP_001373065.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC4A5	ENST00000394019.7	TSL:5 MANE Select	c.3268G>A	p.Val1090Ile	missense	Exon 29 of 31	ENSP00000377587.2	Q9BY07-3
SLC4A5	ENST00000377632.5	TSL:1	c.3025G>A	p.Val1009Ile	missense	Exon 22 of 23	ENSP00000366859.1	Q9BY07-4
SLC4A5	ENST00000358683.8	TSL:1	c.2962G>A	p.Val988Ile	missense	Exon 23 of 24	ENSP00000351513.4	Q9BY07-7

Frequencies

GnomAD3 genomes

AF:

0.0229

AC:

3475

AN:

152002

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00568

Gnomad AMI

AF:

0.0143

Gnomad AMR

AF:

0.0243

Gnomad ASJ

AF:

0.0363

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00851

Gnomad FIN

AF:

0.0440

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0318

Gnomad OTH

AF:

0.0282

GnomAD2 exomes

AF:

0.0237

AC:

5910

AN:

249710

AF XY:

0.0241

show subpopulations

Gnomad AFR exome

AF:

0.00507

Gnomad AMR exome

AF:

0.0175

Gnomad ASJ exome

AF:

0.0341

Gnomad EAS exome

AF:

0.0000546

Gnomad FIN exome

AF:

0.0392

Gnomad NFE exome

AF:

0.0319

Gnomad OTH exome

AF:

0.0260

GnomAD4 exome

AF:

0.0288

AC:

41995

AN:

1459872

Hom.:

725

Cov.:

AF XY:

0.0283

AC XY:

20521

AN XY:

726210

show subpopulations

African (AFR)

AF:

0.00476

AC:

159

AN:

33386

American (AMR)

AF:

0.0184

AC:

819

AN:

44516

Ashkenazi Jewish (ASJ)

AF:

0.0319

AC:

830

AN:

26046

East Asian (EAS)

AF:

0.0000505

AC:

AN:

39632

South Asian (SAS)

AF:

0.00886

AC:

761

AN:

85938

European-Finnish (FIN)

AF:

0.0381

AC:

2035

AN:

53388

Middle Eastern (MID)

AF:

0.0201

AC:

116

AN:

5758

European-Non Finnish (NFE)

AF:

0.0321

AC:

35622

AN:

1110896

Other (OTH)

AF:

0.0274

AC:

1651

AN:

60312

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

1836

3673

5509

7346

9182

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1304

2608

3912

5216

6520

<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:

0.0228

AC:

3469

AN:

152108

Hom.:

Cov.:

AF XY:

0.0232

AC XY:

1725

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.00567

AC:

235

AN:

41480

American (AMR)

AF:

0.0242

AC:

369

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.0363

AC:

126

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00790

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.0440

AC:

464

AN:

10552

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0318

AC:

2161

AN:

68018

Other (OTH)

AF:

0.0275

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

171

341

512

682

853

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

126

168

210

<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:

0.0287

Hom.:

172

Bravo

AF:

0.0213

TwinsUK

AF:

0.0299

AC:

111

ALSPAC

AF:

0.0275

AC:

106

ESP6500AA

AF:

0.00749

AC:

ESP6500EA

AF:

0.0338

AC:

291

ExAC

AF:

0.0239

AC:

2901

Asia WGS

AF:

0.00491

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.041

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.17

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.79

MetaRNN

Benign

0.0025

MetaSVM

Benign

-0.82

MutationAssessor

Benign

0.81

PhyloP100

0.60

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.22

REVEL

Benign

0.18

Sift

Benign

0.30

Sift4G

Benign

0.75

Polyphen

0.0010

Vest4

0.10

MPC

0.21

ClinPred

0.0027

GERP RS

5.0

Varity_R

0.045

gMVP

0.14

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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