rs148961885

Variant names:

• chr4-71557709-C-CA
• rs148961885
• NM_001098484.3:c.2764-2dupA

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PVS1_Moderate BP6 BS1 BS2

The NM_001098484.3(SLC4A4):​c.2764-2dupA variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000853 in 1,612,524 control chromosomes in the GnomAD database, including 14 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0046 (8 hom., cov: 32)
  • Exomes 𝑓: 0.00046 (6 hom.)
• Consequence: SLC4A4 NM_001098484.3 splice_acceptor, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 9.32
• 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: PanelApp Australia, G2P, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.053703703 fraction of the gene. Cryptic splice site detected, with MaxEntScore 8.1, offset of 0 (no position change), new splice context is: tttcctctttcctccccaAGttc. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• BP6: Variant 4-71557709-C-CA is Benign according to our data. Variant chr4-71557709-C-CA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 349555.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00458 (696/152086) while in subpopulation AFR AF = 0.0157 (654/41524). AF 95% confidence interval is 0.0148. There are 8 homozygotes in GnomAd4. There are 322 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC4A4	NM_001098484.3	MANE Select	c.2764-2dupA		splice_acceptor intron	N/A	NP_001091954.1	Q9Y6R1-1
	SLC4A4	NM_003759.4	MANE Plus Clinical	c.2632-2dupA		splice_acceptor intron	N/A	NP_003750.1	Q9Y6R1-2
	SLC4A4	NM_001440629.1		c.2857-2dupA		splice_acceptor intron	N/A	NP_001427558.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC4A4	ENST00000264485.11	TSL:1 MANE Select	c.2764-3_2764-2insA		splice_acceptor intron	N/A	ENSP00000264485.5	Q9Y6R1-1
	SLC4A4	ENST00000340595.4	TSL:1 MANE Plus Clinical	c.2632-3_2632-2insA		splice_acceptor intron	N/A	ENSP00000344272.3	Q9Y6R1-2
	SLC4A4	ENST00000351898.10	TSL:1	c.2512-3_2512-2insA		splice_acceptor intron	N/A	ENSP00000307349.7	Q9Y6R1-4

Frequencies

GnomAD3 genomes AF: 0.00458 AC: 696 AN: 151968 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0158

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00130 AC: 324 AN: 250076 AF XY: 0.000903

Gnomad AFR exome AF: 0.0177

Gnomad AMR exome AF: 0.000784

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000355

Gnomad OTH exome AF: 0.000657

GnomAD4 exome AF: 0.000465 AC: 679 AN: 1460438 Hom.: 6 Cov.: 32 AF XY: 0.000392 AC XY: 285 AN XY: 726544

African (AFR) AF: 0.0167 AC: 558 AN: 33378

American (AMR) AF: 0.000964 AC: 43 AN: 44602

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26086

East Asian (EAS) AF: 0.00 AC: 0 AN: 39612

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53340

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5756

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111164

Other (OTH) AF: 0.00113 AC: 68 AN: 60268

GnomAD4 genome AF: 0.00458 AC: 696 AN: 152086 Hom.: 8 Cov.: 32 AF XY: 0.00433 AC XY: 322 AN XY: 74324

African (AFR) AF: 0.0157 AC: 654 AN: 41524

American (AMR) AF: 0.00203 AC: 31 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5118

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67932

Other (OTH) AF: 0.00426 AC: 9 AN: 2112

Alfa AF: 0.00232 Hom.: 0

Bravo AF: 0.00530

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	1	-	Autosomal recessive proximal renal tubular acidosis (1)
-	-	1	SLC4A4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.3
Mutation Taster		=96/4	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: rs148961885; hg19: chr4-72423426;