rs78937798

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
• Publications: 12 publications found

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 Gene-Disease associations (from GenCC):

• blood group, kidd system

  Inheritance: AD Classification: LIMITED Submitted by: PanelApp Australia

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 VariationId is 17718.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 70 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015865.7. 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
	SLC14A1	NM_015865.7	MANE Select	c.342-1G>A		splice_acceptor intron	N/A	NP_056949.4	Q13336-1
	SLC14A1	NM_001128588.4		c.510-1G>A		splice_acceptor intron	N/A	NP_001122060.3	Q13336-2
	SLC14A1	NM_001146037.1		c.510-1G>A		splice_acceptor intron	N/A	NP_001139509.1	Q13336-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC14A1	ENST00000321925.9	TSL:1 MANE Select	c.342-1G>A		splice_acceptor intron	N/A	ENSP00000318546.4	Q13336-1
	SLC14A1	ENST00000586142.5	TSL:1	c.342-1G>A		splice_acceptor intron	N/A	ENSP00000470476.1	Q13336-1
	SLC14A1	ENST00000589700.5	TSL:1	c.342-1G>A		splice_acceptor intron	N/A	ENSP00000465044.1	E9NSU1

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

African (AFR) AF: 0.0000896 AC: 3 AN: 33478

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00464 AC: 184 AN: 39696

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111924

Other (OTH) 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

African (AFR) AF: 0.0000482 AC: 2 AN: 41532

American (AMR) AF: 0.000589 AC: 9 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.0105 AC: 54 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68018

Other (OTH) AF: 0.00190 AC: 4 AN: 2110

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

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Jk-null variant (1)
1	-	-	SLC14A1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		8.9
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

Other links and lift over

dbSNP: rs78937798; hg19: chr18-43314238;