chr18-45734273-G-A

Variant names:

• chr18-45734273-G-A
• rs78937798
• NM_015865.7:c.342-1G>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 6P and 1B. PVS1_Strong PP5_Moderate BS2_Supporting

The NM_015865.7(SLC14A1):​c.342-1G>A variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00024 in 1,613,980 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: 𝑓 0.00046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (7 hom.)
• Consequence: SLC14A1 NM_015865.7 splice_acceptor, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 8.88

Genes affected

SLC14A1 (HGNC:10918): (solute carrier family 14 member 1 (Kidd blood group)) The protein encoded by this gene is a membrane transporter that mediates urea transport in erythrocytes. This gene forms the basis for the Kidd blood group system. [provided by RefSeq, Mar 2009]

ENSG00000288545 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.11025641 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.7, offset of 1, new splice context is: tgtgtctcttgccccacaAGtca. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PP5: Variant 18-45734273-G-A is Pathogenic according to our data. Variant chr18-45734273-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 17718.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 7 BG geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC14A1	NM_015865.7	c.342-1G>A		splice_acceptor_variant, intron_variant	Intron 4 of 9	ENST00000321925.9	NP_056949.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC14A1	ENST00000321925.9	c.342-1G>A		splice_acceptor_variant, intron_variant	Intron 4 of 9	1	NM_015865.7	ENSP00000318546.4

Frequencies

GnomAD3 genomes AF: 0.000454 AC: 69 AN: 152094 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0104

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000819 AC: 206 AN: 251418 AF XY: 0.000817

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0107

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000218 AC: 318 AN: 1461768 Hom.: 7 Cov.: 32 AF XY: 0.000197 AC XY: 143 AN XY: 727182

Gnomad4 AFR exome AF: 0.0000896 AC: 3 AN: 33478

Gnomad4 AMR exome AF: 0.0000447 AC: 2 AN: 44724

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26136

Gnomad4 EAS exome AF: 0.00464 AC: 184 AN: 39696

Gnomad4 SAS exome AF: 0.0000116 AC: 1 AN: 86250

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53408

Gnomad4 NFE exome AF: 0.00000180 AC: 2 AN: 1111924

Gnomad4 Remaining exome AF: 0.00209 AC: 126 AN: 60384

GnomAD4 genome AF: 0.000460 AC: 70 AN: 152212 Hom.: 0 Cov.: 32 AF XY: 0.000443 AC XY: 33 AN XY: 74418

Gnomad4 AFR AF: 0.0000482 AC: 0.0000481556 AN: 0.0000481556

Gnomad4 AMR AF: 0.000589 AC: 0.00058862 AN: 0.00058862

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.0105 AC: 0.010453 AN: 0.010453

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000147 AC: 0.000014702 AN: 0.000014702

Gnomad4 OTH AF: 0.00190 AC: 0.00189573 AN: 0.00189573

Alfa AF: 0.000535 Hom.: 5

Bravo AF: 0.000495

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000700 AC: 85

Asia WGS AF: 0.00722 AC: 25 AN: 3478

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Jk-null variant Pathogenic:1

May 22, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

SLC14A1-related disorder Pathogenic:1

May 17, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SLC14A1 c.342-1G>A variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant is predicted to disrupt the consensus AG splice-acceptor site in SLC14A1 near the intron 4 – exon 5 boundary and has been reported in affected individuals (Lucien et al. 1998. PubMed ID: 9582331; Hou et al. 2020. PubMed ID: 31980526). SLC14A1 encodes a urea transporter that is found in the kidney and on red blood cells. The blood type Jk-null is defined by a loss of the SLC14A1 protein on red blood cells. The Jk-null blood type is not defined by any obvious clinical presentation, but patients may have a urine concentration defect (Sands et al. 1992. PubMed ID: 1498276). Patients with two deleterious variants in a trans configuration may have the Jk-null phenotype and could develop alloantibodies against the Jk antigen during pregnancy or after transfusion with Jk+ red blood cells that may cause hemolysis (Lucien et al. 2002. PubMed ID: 11807016). This variant is reported in 1.1% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/18-43314238-G-A). Variants that disrupt the consensus splice acceptor site in SLC14A1 are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.040	T
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	26
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.98	D
GERP RS		5.5
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		0.93		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.93		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs78937798; hg19: chr18-43314238;