dbSNP rs36081793: SLC4A5:p.Val1090Phe (chr2-74222931-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_133478.3(SLC4A5):c.3268G>T(p.Val1090Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,252 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SLC4A5
NM_133478.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.601

Publications

0 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: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.26866645).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
SLC4A5	NM_133478.3 link	c.3268G>T	p.Val1090Phe	missense_variant	Exon 29 of 31	ENST00000394019.7	NP_597812.1
SLC4A5	NM_021196.3 link	c.3316G>T	p.Val1106Phe	missense_variant	Exon 25 of 26		NP_067019.3
SLC4A5	NM_001386136.1 link	c.2920G>T	p.Val974Phe	missense_variant	Exon 23 of 25		NP_001373065.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
SLC4A5	ENST00000394019.7 link	c.3268G>T	p.Val1090Phe	missense_variant	Exon 29 of 31	5	NM_133478.3	ENSP00000377587.2
ENSG00000264324	ENST00000451608.2 link	n.*3920G>T		non_coding_transcript_exon_variant	Exon 35 of 39	5		ENSP00000416453.2
ENSG00000264324	ENST00000451608.2 link	n.*3920G>T		3_prime_UTR_variant	Exon 35 of 39	5		ENSP00000416453.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460252

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726362

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33386

American (AMR)

AF:

0.00

AC:

AN:

44524

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26050

East Asian (EAS)

AF:

0.00

AC:

AN:

39632

South Asian (SAS)

AF:

0.00

AC:

AN:

85938

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111246

Other (OTH)

AF:

0.00

AC:

AN:

60318

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.089

.;.;T;.;.;T

Eigen

Benign

0.10

Eigen_PC

Benign

0.17

FATHMM_MKL

Benign

0.74

LIST_S2

Uncertain

0.90

.;D;D;D;D;.

M_CAP

Uncertain

0.24

MetaRNN

Benign

0.27

T;T;T;T;T;T

MetaSVM

Uncertain

-0.11

MutationAssessor

Benign

0.81

.;.;L;.;.;L

PhyloP100

0.60

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-1.6

N;.;.;N;N;N

REVEL

Uncertain

0.45

Sift

Uncertain

0.016

D;.;.;D;D;D

Sift4G

Benign

0.27

T;T;T;T;T;T

Polyphen

0.26

B;B;P;P;P;P

Vest4

0.47

MutPred

0.12

.;.;Loss of sheet (P = 0.0817);.;.;Loss of sheet (P = 0.0817);

MVP

0.51

MPC

0.45

ClinPred

0.73

GERP RS

5.0

Varity_R

0.16

gMVP

0.48

Mutation Taster

=90/10

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.19

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over