rs41265669

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_001098484.3(SLC4A4):c.149G>C(p.Gly50Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00259 in 1,613,320 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0027 ( 8 hom. )

Consequence

SLC4A4
NM_001098484.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 7.35

Publications

6 publications found

Variant links:

Genes affected

SLC4A4 (HGNC:11030): (solute carrier family 4 member 4) This gene encodes a sodium bicarbonate cotransporter (NBC) involved in the regulation of bicarbonate secretion and absorption and intracellular pH. Mutations in this gene are associated with proximal renal tubular acidosis. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2008]

SLC4A4 Gene-Disease associations (from GenCC):

autosomal recessive proximal renal tubular acidosis
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, G2P, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)

SLC4A4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0113144815).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00176 (267/152008) while in subpopulation NFE AF = 0.00296 (201/67970). AF 95% confidence interval is 0.00262. There are 0 homozygotes in GnomAd4. There are 110 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 8 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001098484.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC4A4	NM_001098484.3	MANE Select	c.149G>C	p.Gly50Ala	missense	Exon 3 of 26	NP_001091954.1	Q9Y6R1-1
SLC4A4	NM_001440629.1		c.242G>C	p.Gly81Ala	missense	Exon 3 of 26	NP_001427558.1
SLC4A4	NM_001134742.2		c.149G>C	p.Gly50Ala	missense	Exon 3 of 25	NP_001128214.1	A5JJ20

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC4A4	ENST00000264485.11	TSL:1 MANE Select	c.149G>C	p.Gly50Ala	missense	Exon 3 of 26	ENSP00000264485.5	Q9Y6R1-1
SLC4A4	ENST00000351898.10	TSL:1	c.149G>C	p.Gly50Ala	missense	Exon 3 of 24	ENSP00000307349.7	Q9Y6R1-4
SLC4A4	ENST00000514331.1	TSL:1	n.78G>C		non_coding_transcript_exon	Exon 1 of 12

Frequencies

GnomAD3 genomes

AF:

0.00176

AC:

268

AN:

151888

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000702

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.000853

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000830

Gnomad FIN

AF:

0.000945

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00297

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.00157

AC:

390

AN:

249120

AF XY:

0.00152

show subpopulations

Gnomad AFR exome

AF:

0.000711

Gnomad AMR exome

AF:

0.000580

Gnomad ASJ exome

AF:

0.000696

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000789

Gnomad NFE exome

AF:

0.00289

Gnomad OTH exome

AF:

0.00116

GnomAD4 exome

AF:

0.00268

AC:

3914

AN:

1461312

Hom.:

Cov.:

AF XY:

0.00256

AC XY:

1860

AN XY:

726968

show subpopulations

African (AFR)

AF:

0.000598

AC:

AN:

33452

American (AMR)

AF:

0.000962

AC:

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.000651

AC:

AN:

26118

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00103

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00327

AC:

3634

AN:

1111556

Other (OTH)

AF:

0.00232

AC:

140

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

202

404

605

807

1009

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

142

284

426

568

710

<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:

0.00176

AC:

267

AN:

152008

Hom.:

Cov.:

AF XY:

0.00148

AC XY:

110

AN XY:

74312

show subpopulations

African (AFR)

AF:

0.000700

AC:

AN:

41454

American (AMR)

AF:

0.000852

AC:

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5152

South Asian (SAS)

AF:

0.000831

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.000945

AC:

AN:

10582

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00296

AC:

201

AN:

67970

Other (OTH)

AF:

0.00142

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00241

Hom.:

Bravo

AF:

0.00184

TwinsUK

AF:

0.00378

AC:

ALSPAC

AF:

0.00389

AC:

ESP6500AA

AF:

0.000516

AC:

ESP6500EA

AF:

0.00279

AC:

ExAC

AF:

0.00157

AC:

190

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00191

EpiControl

AF:

0.00267

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Autosomal recessive proximal renal tubular acidosis (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.16

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.37

Eigen

Benign

0.17

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.029

MetaRNN

Benign

0.011

MetaSVM

Benign

-0.47

MutationAssessor

Benign

1.8

PhyloP100

7.4

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-2.0

REVEL

Benign

0.29

Sift

Benign

0.26

Sift4G

Uncertain

0.016

Polyphen

0.034

Vest4

0.26

MVP

0.41

MPC

0.60

ClinPred

0.042

GERP RS

5.7

Varity_R

0.25

gMVP

0.30

Mutation Taster

=73/27

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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