NM_000342.4:c.*1227A>C

Variant names:

• chr17-44249231-T-G
• rs141425539
• NM_000342.4:c.*1227A>C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_000342.4(SLC4A1):​c.*1227A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00381 in 448,152 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0030 (2 hom., cov: 29)
  • Exomes 𝑓: 0.0043 (12 hom.)
• Consequence: SLC4A1 NM_000342.4 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, single submitter B:3
• Conservation: PhyloP100: 1.22

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 17-44249231-T-G is Benign according to our data. Variant chr17-44249231-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 323486.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-44249231-T-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00295 (449/152196) while in subpopulation SAS AF= 0.00663 (32/4828). AF 95% confidence interval is 0.00483. There are 2 homozygotes in gnomad4. There are 232 alleles in male gnomad4 subpopulation. Median coverage is 29. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR,BG gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC4A1	NM_000342.4	c.*1227A>C		3_prime_UTR_variant	Exon 20 of 20	ENST00000262418.12	NP_000333.1
SLC4A1	XM_011525129.3	c.*1227A>C		3_prime_UTR_variant	Exon 19 of 19		XP_011523431.1
SLC4A1	XM_005257593.6	c.*1227A>C		3_prime_UTR_variant	Exon 18 of 18		XP_005257650.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC4A1	ENST00000262418	c.*1227A>C		3_prime_UTR_variant	Exon 20 of 20	1	NM_000342.4	ENSP00000262418.6
SLC4A1	ENST00000399246	c.*1227A>C		3_prime_UTR_variant	Exon 15 of 15	5		ENSP00000382190.3

Frequencies

GnomAD3 genomes AF: 0.00296 AC: 450 AN: 152078 Hom.: 2 Cov.: 29

Gnomad AFR AF: 0.000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000590

Gnomad ASJ AF: 0.00750

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00662

Gnomad FIN AF: 0.0108

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00344

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00389 AC: 473 AN: 121516 Hom.: 3 AF XY: 0.00422 AC XY: 281 AN XY: 66548

Gnomad AFR exome AF: 0.000341

Gnomad AMR exome AF: 0.000458

Gnomad ASJ exome AF: 0.00692

Gnomad EAS exome AF: 0.000103

Gnomad SAS exome AF: 0.00709

Gnomad FIN exome AF: 0.00898

Gnomad NFE exome AF: 0.00444

Gnomad OTH exome AF: 0.00184

GnomAD4 exome AF: 0.00425 AC: 1259 AN: 295956 Hom.: 12 Cov.: 0 AF XY: 0.00466 AC XY: 788 AN XY: 169094

Gnomad4 AFR exome AF: 0.000629

Gnomad4 AMR exome AF: 0.000442

Gnomad4 ASJ exome AF: 0.00657

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00681

Gnomad4 FIN exome AF: 0.00903

Gnomad4 NFE exome AF: 0.00385

Gnomad4 OTH exome AF: 0.00425

GnomAD4 genome AF: 0.00295 AC: 449 AN: 152196 Hom.: 2 Cov.: 29 AF XY: 0.00312 AC XY: 232 AN XY: 74410

Gnomad4 AFR AF: 0.000723

Gnomad4 AMR AF: 0.000589

Gnomad4 ASJ AF: 0.00750

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00663

Gnomad4 FIN AF: 0.0108

Gnomad4 NFE AF: 0.00344

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.00281 Hom.: 0

Bravo AF: 0.00209

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal dominant distal renal tubular acidosis Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Hereditary spherocytosis type 4 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Hemolytic anemia Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	14
DANN	Benign	0.94

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

Publications

LitVar

Other links and lift over

dbSNP: rs141425539; hg19: chr17-42326599;