chr18-45734273-G-A

Position:

chr18-45734273-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 7P and 1B. PVS1_StrongPP3PP5_ModerateBS2_Supporting

The ENST00000321925.9(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
ENST00000321925.9 splice_acceptor

Scores

Splicing: ADA: 0.9999

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 8.88

Variant links:

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]

SLC14A1 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product 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

Multiple lines of computational evidence support a deleterious effect 7: BayesDel_noAF, Cadd, dbscSNV1_ADA, dbscSNV1_RF, max_spliceai, Eigen, phyloP100way_vertebrate [when BayesDel_addAF, MutationTaster was below the threshold]

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/exons	MANE	Protein	UniProt
SLC14A1	NM_015865.7 linkuse as main transcript	c.342-1G>A		splice_acceptor_variant		ENST00000321925.9	NP_056949.4
LOC105372093	XR_935423.3 linkuse as main transcript	n.826+3193C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC14A1	ENST00000321925.9 linkuse as main transcript	c.342-1G>A		splice_acceptor_variant		1	NM_015865.7	ENSP00000318546	P1	Q13336-1
	ENST00000589510.5 linkuse as main transcript	n.160+3193C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.000454

AC:

AN:

152094

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.000817

AC XY:

111

AN XY:

135882

show subpopulations

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.:

Cov.:

AF XY:

0.000197

AC XY:

143

AN XY:

727182

show subpopulations

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:

AN:

152212

Hom.:

Cov.:

AF XY:

0.000443

AC XY:

AN XY:

74418

show subpopulations

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.:

Bravo

AF:

0.000495

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000700

AC:

Asia WGS

AF:

0.00722

AC:

AN:

3478

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

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

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Pathogenic

0.98

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over