18-45734273-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1_Strong PP3_Strong PP5_Moderate

The NM_015865.7(SLC14A1):c.342-1G>A variant causes a splice acceptor 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
• 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]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.10940171 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.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC14A1	NM_015865.7	c.342-1G>A		splice_acceptor_variant		ENST00000321925.9
LOC105372093	XR_935423.3	n.826+3193C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC14A1	ENST00000321925.9	c.342-1G>A		splice_acceptor_variant		1	NM_015865.7	P1
	ENST00000589510.5	n.160+3193C>T		intron_variant, non_coding_transcript_variant		5

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

GnomAD3 exomes AF: 0.000819 AC: 206 AN: 251418 Hom.: 1 AF XY: 0.000817 AC XY: 111 AN XY: 135882

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 SAS exome AF: 0.00

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

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00464

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00209

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

Gnomad4 AMR AF: 0.000589

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0105

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.000533 Hom.: 2

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

Pathogenic, no assertion criteria provided

literature only

OMIM

May 22, 1998

- -

SLC14A1-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 17, 2023

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
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
GERP RS		5.5

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;