rs6427419

Positions:

• chr1-158088319-C-A
• chr1-158088319-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000359209.11(KIRREL1):​c.917-8C>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.514 in 1,608,044 control chromosomes in the GnomAD database, including 221,194 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.42 (16497 hom., cov: 30)
  • Exomes 𝑓: 0.52 (204697 hom.)
• Consequence: KIRREL1 ENST00000359209.11 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.003611
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.339

Genes affected

KIRREL1 (HGNC:15734): (kirre like nephrin family adhesion molecule 1) NEPH1 is a member of the nephrin-like protein family, which includes NEPH2 (MIM 607761) and NEPH3 (MIM 607762). The cytoplasmic domains of these proteins interact with the C terminus of podocin (NPHS2; MIM 604766), and the genes are expressed in kidney podocytes, cells involved in ensuring size- and charge-selective ultrafiltration (Sellin et al., 2003 [PubMed 12424224]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.663 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIRREL1	NM_018240.7	c.917-8C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000359209.11	NP_060710.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIRREL1	ENST00000359209.11	c.917-8C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_018240.7	ENSP00000352138	P1
KIRREL1	ENST00000360089.8	c.425-8C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		ENSP00000353202
KIRREL1	ENST00000368172.2	c.565-8C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		2		ENSP00000357154
KIRREL1	ENST00000368173.7	c.617-8C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		2		ENSP00000357155

Frequencies

GnomAD3 genomes AF: 0.421 AC: 63854 AN: 151670 Hom.: 16480 Cov.: 30

Gnomad AFR AF: 0.112

Gnomad AMI AF: 0.639

Gnomad AMR AF: 0.544

Gnomad ASJ AF: 0.382

Gnomad EAS AF: 0.682

Gnomad SAS AF: 0.588

Gnomad FIN AF: 0.584

Gnomad MID AF: 0.369

Gnomad NFE AF: 0.524

Gnomad OTH AF: 0.419

GnomAD3 exomes AF: 0.533 AC: 131791 AN: 247138 Hom.: 37591 AF XY: 0.536 AC XY: 71651 AN XY: 133564

Gnomad AFR exome AF: 0.0975

Gnomad AMR exome AF: 0.667

Gnomad ASJ exome AF: 0.390

Gnomad EAS exome AF: 0.689

Gnomad SAS exome AF: 0.578

Gnomad FIN exome AF: 0.581

Gnomad NFE exome AF: 0.523

Gnomad OTH exome AF: 0.521

GnomAD4 exome AF: 0.523 AC: 762221 AN: 1456252 Hom.: 204697 Cov.: 51 AF XY: 0.525 AC XY: 380338 AN XY: 724154

Gnomad4 AFR exome AF: 0.0927

Gnomad4 AMR exome AF: 0.655

Gnomad4 ASJ exome AF: 0.390

Gnomad4 EAS exome AF: 0.672

Gnomad4 SAS exome AF: 0.581

Gnomad4 FIN exome AF: 0.579

Gnomad4 NFE exome AF: 0.524

Gnomad4 OTH exome AF: 0.498

GnomAD4 genome AF: 0.421 AC: 63880 AN: 151792 Hom.: 16497 Cov.: 30 AF XY: 0.428 AC XY: 31770 AN XY: 74174

Gnomad4 AFR AF: 0.112

Gnomad4 AMR AF: 0.545

Gnomad4 ASJ AF: 0.382

Gnomad4 EAS AF: 0.682

Gnomad4 SAS AF: 0.589

Gnomad4 FIN AF: 0.584

Gnomad4 NFE AF: 0.524

Gnomad4 OTH AF: 0.423

Alfa AF: 0.502 Hom.: 43273

Bravo AF: 0.406

Asia WGS AF: 0.607 AC: 2112 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	3.6
DANN	Benign	0.59

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0036
dbscSNV1_RF	Benign	0.064
SpliceAI score (max)		0.010		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: rs6427419; hg19: chr1-158058109;