17-44259879-C-T

Variant names:

• chr17-44259879-C-T
• rs147390654
• NM_000342.4:c.539G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000342.4(SLC4A1):​c.539G>A​(p.Arg180His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00461 in 1,614,046 control chromosomes in the GnomAD database, including 28 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R180C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0029 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0048 (28 hom.)
• Consequence: SLC4A1 NM_000342.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:8 O:1
• Conservation: PhyloP100: -0.714
• Publications: 10 publications found

Genes affected

SLC4A1 (HGNC:11027): (solute carrier family 4 member 1 (Diego blood group)) The protein encoded by this gene is part of the anion exchanger (AE) family and is expressed in the erythrocyte plasma membrane, where it functions as a chloride/bicarbonate exchanger involved in carbon dioxide transport from tissues to lungs. The protein comprises two domains that are structurally and functionally distinct. The N-terminal 40kDa domain is located in the cytoplasm and acts as an attachment site for the red cell skeleton by binding ankyrin. The glycosylated C-terminal membrane-associated domain contains 12-14 membrane spanning segments and carries out the stilbene disulphonate-sensitive exchange transport of anions. The cytoplasmic tail at the extreme C-terminus of the membrane domain binds carbonic anhydrase II. The encoded protein associates with the red cell membrane protein glycophorin A and this association promotes the correct folding and translocation of the exchanger. This protein is predominantly dimeric but forms tetramers in the presence of ankyrin. Many mutations in this gene are known in man, and these mutations can lead to two types of disease: destabilization of red cell membrane leading to hereditary spherocytosis, and defective kidney acid secretion leading to distal renal tubular acidosis. Other mutations that do not give rise to disease result in novel blood group antigens, which form the Diego blood group system. Southeast Asian ovalocytosis (SAO, Melanesian ovalocytosis) results from the heterozygous presence of a deletion in the encoded protein and is common in areas where Plasmodium falciparum malaria is endemic. One null mutation in this gene is known, resulting in very severe anemia and nephrocalcinosis. [provided by RefSeq, Jul 2008]

SLC4A1 Gene-Disease associations (from GenCC):

• autosomal dominant distal renal tubular acidosis

  Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
• cryohydrocytosis

  Inheritance: AD, Unknown Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia
• hereditary spherocytosis type 4

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• southeast Asian ovalocytosis

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• renal tubular acidosis, distal, 4, with hemolytic anemia

  Inheritance: AR, AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Orphanet
• dehydrated hereditary stomatocytosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary spherocytosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.024107307).
• BP6: Variant 17-44259879-C-T is Benign according to our data. Variant chr17-44259879-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 255914.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00288 (439/152200) while in subpopulation NFE AF = 0.00457 (311/68014). AF 95% confidence interval is 0.00415. There are 0 homozygotes in GnomAd4. There are 211 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 28 AD,AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000342.4. 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
	SLC4A1	NM_000342.4	MANE Select	c.539G>A	p.Arg180His	missense	Exon 7 of 20	NP_000333.1	P02730-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC4A1	ENST00000262418.12	TSL:1 MANE Select	c.539G>A	p.Arg180His	missense	Exon 7 of 20	ENSP00000262418.6	P02730-1
	SLC4A1	ENST00000399246.3	TSL:5	c.539G>A	p.Arg180His	missense	Exon 7 of 15	ENSP00000382190.3	A0A0A0MS98

Frequencies

GnomAD3 genomes AF: 0.00289 AC: 439 AN: 152082 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00836

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00270

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00457

Gnomad OTH AF: 0.00241

GnomAD2 exomes AF: 0.00342 AC: 860 AN: 251454 AF XY: 0.00345

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.00243

Gnomad ASJ exome AF: 0.00962

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000878

Gnomad NFE exome AF: 0.00490

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00479 AC: 7003 AN: 1461846 Hom.: 28 Cov.: 33 AF XY: 0.00475 AC XY: 3453 AN XY: 727224

African (AFR) AF: 0.00108 AC: 36 AN: 33480

American (AMR) AF: 0.00246 AC: 110 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00945 AC: 247 AN: 26136

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39698

South Asian (SAS) AF: 0.00268 AC: 231 AN: 86256

European-Finnish (FIN) AF: 0.000843 AC: 45 AN: 53404

Middle Eastern (MID) AF: 0.00312 AC: 18 AN: 5768

European-Non Finnish (NFE) AF: 0.00547 AC: 6080 AN: 1111986

Other (OTH) AF: 0.00381 AC: 230 AN: 60394

GnomAD4 genome AF: 0.00288 AC: 439 AN: 152200 Hom.: 0 Cov.: 32 AF XY: 0.00284 AC XY: 211 AN XY: 74406

African (AFR) AF: 0.00101 AC: 42 AN: 41514

American (AMR) AF: 0.00216 AC: 33 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00836 AC: 29 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5172

South Asian (SAS) AF: 0.00270 AC: 13 AN: 4816

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10614

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00457 AC: 311 AN: 68014

Other (OTH) AF: 0.00238 AC: 5 AN: 2100

Alfa AF: 0.00343 Hom.: 7

Bravo AF: 0.00323

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00593 AC: 51

ExAC AF: 0.00355 AC: 431

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00534

EpiControl AF: 0.00504

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	4	not provided (5)
-	1	2	not specified (3)
-	1	-	Autosomal dominant distal renal tubular acidosis (1)
-	-	1	Hemolytic anemia (1)
-	-	1	Hereditary spherocytosis type 4 (1)
-	1	-	Renal tubular acidosis, distal, 4, with hemolytic anemia;CN280572:Autosomal dominant distal renal tubular acidosis (1)
-	-	-	Hereditary spherocytosis type 4;C5436235:Renal tubular acidosis, distal, 4, with hemolytic anemia;CN280572:Autosomal dominant distal renal tubular acidosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	4.5
DANN	Benign	0.89
DEOGEN2	Benign	0.22	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.064	N
LIST_S2	Benign	0.65	T
M_CAP	Pathogenic	0.40	D
MetaRNN	Benign	0.024	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.57	N
PhyloP100		-0.71
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.29	N
REVEL	Uncertain	0.51
Sift	Benign	0.21	T
Sift4G	Benign	0.18	T
Polyphen		0.0	B
Vest4		0.17
MVP		0.98
MPC		0.43
ClinPred		0.00015	T
GERP RS		-2.0
Varity_R		0.11
gMVP		0.38
Mutation Taster		=98/2	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: rs147390654; hg19: chr17-42337247;