rs188304864

Variant names:

• chr4-71255260-T-C
• rs188304864
• NM_001098484.3:c.114T>C

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_001098484.3(SLC4A4):​c.114T>C​(p.Ser38Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00251 in 1,613,192 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (6 hom.)
• Consequence: SLC4A4 NM_001098484.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.47
• Publications: 0 publications found

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: G2P, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 4-71255260-T-C is Benign according to our data. Variant chr4-71255260-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 2654800.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=2.47 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0018 (273/151930) while in subpopulation NFE AF = 0.00262 (178/67948). AF 95% confidence interval is 0.0023. There are 0 homozygotes in GnomAd4. There are 134 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 6 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC4A4	NM_001098484.3	MANE Select	c.114T>C	p.Ser38Ser	synonymous	Exon 3 of 26	NP_001091954.1	Q9Y6R1-1
	SLC4A4	NM_001440629.1		c.207T>C	p.Ser69Ser	synonymous	Exon 3 of 26	NP_001427558.1
	SLC4A4	NM_001134742.2		c.114T>C	p.Ser38Ser	synonymous	Exon 3 of 25	NP_001128214.1	A5JJ20

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC4A4	ENST00000264485.11	TSL:1 MANE Select	c.114T>C	p.Ser38Ser	synonymous	Exon 3 of 26	ENSP00000264485.5	Q9Y6R1-1
	SLC4A4	ENST00000351898.10	TSL:1	c.114T>C	p.Ser38Ser	synonymous	Exon 3 of 24	ENSP00000307349.7	Q9Y6R1-4
	SLC4A4	ENST00000514331.1	TSL:1	n.43T>C		non_coding_transcript_exon	Exon 1 of 12

Frequencies

GnomAD3 genomes AF: 0.00180 AC: 273 AN: 151812 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000412

Gnomad AMI AF: 0.0286

Gnomad AMR AF: 0.00256

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00262

Gnomad OTH AF: 0.00529

GnomAD2 exomes AF: 0.00150 AC: 375 AN: 249250 AF XY: 0.00149

Gnomad AFR exome AF: 0.000517

Gnomad AMR exome AF: 0.00217

Gnomad ASJ exome AF: 0.000894

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000278

Gnomad NFE exome AF: 0.00234

Gnomad OTH exome AF: 0.00215

GnomAD4 exome AF: 0.00259 AC: 3778 AN: 1461262 Hom.: 6 Cov.: 33 AF XY: 0.00246 AC XY: 1790 AN XY: 726960

African (AFR) AF: 0.000359 AC: 12 AN: 33446

American (AMR) AF: 0.00217 AC: 97 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.000651 AC: 17 AN: 26120

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39692

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.000356 AC: 19 AN: 53418

Middle Eastern (MID) AF: 0.000521 AC: 3 AN: 5754

European-Non Finnish (NFE) AF: 0.00312 AC: 3471 AN: 1111500

Other (OTH) AF: 0.00260 AC: 157 AN: 60366

GnomAD4 genome AF: 0.00180 AC: 273 AN: 151930 Hom.: 0 Cov.: 32 AF XY: 0.00180 AC XY: 134 AN XY: 74250

African (AFR) AF: 0.000410 AC: 17 AN: 41432

American (AMR) AF: 0.00256 AC: 39 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4794

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10574

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00262 AC: 178 AN: 67948

Other (OTH) AF: 0.00524 AC: 11 AN: 2100

Alfa AF: 0.00175 Hom.: 0

Bravo AF: 0.00192

EpiCase AF: 0.00240

EpiControl AF: 0.00255

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	9.9
DANN	Benign	0.78
PhyloP100		2.5
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs188304864; hg19: chr4-72120977;