Genetic Variant SLC4A5:p.Val1090Ile (chr2-74222931-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -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. 15/20 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

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 made for transcript

Verdict is Benign. Variant got -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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 54 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC4A5	NM_133478.3 link	c.3268G>A	p.Val1090Ile	missense_variant	Exon 29 of 31	ENST00000394019.7	NP_597812.1	Q9BY07-3
SLC4A5	NM_021196.3 link	c.3316G>A	p.Val1106Ile	missense_variant	Exon 25 of 26		NP_067019.3	Q9BY07-1
SLC4A5	NM_001386136.1 link	c.2920G>A	p.Val974Ile	missense_variant	Exon 23 of 25		NP_001373065.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SLC4A5	ENST00000394019.7 link	c.3268G>A	p.Val1090Ile	missense_variant	Exon 29 of 31	5	NM_133478.3	ENSP00000377587.2	Q9BY07-3
ENSG00000264324	ENST00000451608.2 link	n.*3920G>A		non_coding_transcript_exon_variant	Exon 35 of 39	5		ENSP00000416453.2	E7EWF7
ENSG00000264324	ENST00000451608.2 link	n.*3920G>A		3_prime_UTR_variant	Exon 35 of 39	5		ENSP00000416453.2	E7EWF7

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

GnomAD3 exomes

AF:

0.0237

AC:

5910

AN:

249710

Hom.:

AF XY:

0.0241

AC XY:

3249

AN XY:

134926

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 SAS exome

AF:

0.00932

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

Gnomad4 AFR exome

AF:

0.00476

Gnomad4 AMR exome

AF:

0.0184

Gnomad4 ASJ exome

AF:

0.0319

Gnomad4 EAS exome

AF:

0.0000505

Gnomad4 SAS exome

AF:

0.00886

Gnomad4 FIN exome

AF:

0.0381

Gnomad4 NFE exome

AF:

0.0321

Gnomad4 OTH exome

AF:

0.0274

GnomAD4 genome

AF:

0.0228

AC:

3469

AN:

152108

Hom.:

Cov.:

AF XY:

0.0232

AC XY:

1725

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.00567

Gnomad4 AMR

AF:

0.0242

Gnomad4 ASJ

AF:

0.0363

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00790

Gnomad4 FIN

AF:

0.0440

Gnomad4 NFE

AF:

0.0318

Gnomad4 OTH

AF:

0.0275

Alfa

AF:

0.0292

Hom.:

123

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.041

.;.;T;.;.;T

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.17

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.79

.;T;T;T;T;.

MetaRNN

Benign

0.0025

T;T;T;T;T;T

MetaSVM

Benign

-0.82

MutationAssessor

Benign

0.81

.;.;L;.;.;L

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.22

N;.;.;N;N;N

REVEL

Benign

0.18

Sift

Benign

0.30

T;.;.;T;T;T

Sift4G

Benign

0.75

T;T;T;T;T;T

Polyphen

0.0010

B;B;B;B;B;B

Vest4

0.10

MPC

0.21

ClinPred

0.0027

GERP RS

5.0

Varity_R

0.045

gMVP

0.14

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over