4-71339279-A-G

Variant names:

• chr4-71339279-A-G
• rs545021444
• NM_003759.4:c.31A>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_003759.4(SLC4A4):​c.31A>G​(p.Ser11Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000149 in 1,614,230 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: SLC4A4 NM_003759.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 5.40
• Publications: 1 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06633413).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000105 (16/152340) while in subpopulation AFR AF = 0.000337 (14/41574). AF 95% confidence interval is 0.000204. There are 0 homozygotes in GnomAd4. There are 10 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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003759.4. 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_003759.4	MANE Plus Clinical	c.31A>G	p.Ser11Gly	missense	Exon 1 of 23	NP_003750.1	Q9Y6R1-2
	SLC4A4	NM_001098484.3	MANE Select	c.254-91A>G		intron	N/A	NP_001091954.1	Q9Y6R1-1
	SLC4A4	NM_001440629.1		c.347-91A>G		intron	N/A	NP_001427558.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC4A4	ENST00000340595.4	TSL:1 MANE Plus Clinical	c.31A>G	p.Ser11Gly	missense	Exon 1 of 23	ENSP00000344272.3	Q9Y6R1-2
	SLC4A4	ENST00000512686.5	TSL:1	c.31A>G	p.Ser11Gly	missense	Exon 1 of 11	ENSP00000422400.1	Q9Y6R1-3
	SLC4A4	ENST00000264485.11	TSL:1 MANE Select	c.254-91A>G		intron	N/A	ENSP00000264485.5	Q9Y6R1-1

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152222 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000239 AC: 6 AN: 251486 AF XY: 0.0000147

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461890 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727246

African (AFR) AF: 0.000209 AC: 7 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152340 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74480

African (AFR) AF: 0.000337 AC: 14 AN: 41574

American (AMR) AF: 0.0000653 AC: 1 AN: 15304

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68030

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000109 Hom.: 0

Bravo AF: 0.0000831

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Autosomal recessive proximal renal tubular acidosis (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	11
DANN	Uncertain	0.99
Eigen	Benign	-0.089
Eigen_PC	Benign	0.031
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.39	T
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.066	T
MetaSVM	Benign	-0.52	T
PhyloP100		5.4
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.14
Sift	Benign	0.032	D
Sift4G	Benign	0.38	T
Polyphen		0.010	B
Vest4		0.12
MVP		0.13
ClinPred		0.056	T
GERP RS		4.3
PromoterAI		0.012	Neutral
Mutation Taster		=85/15	polymorphism

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

Other links and lift over

dbSNP: rs545021444; hg19: chr4-72204996;