NM_018240.7:c.917-8C>A

Variant names:

• chr1-158088319-C-A
• rs6427419
• NM_018240.7:c.917-8C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_018240.7(KIRREL1):​c.917-8C>A variant causes a splice region, 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 NM_018240.7 splice_region, intron
• Scores: Splicing: ADA: 0.003611
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.339
• Publications: 17 publications found

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]

KIRREL1 Gene-Disease associations (from GenCC):

• nephrotic syndrome, type 23

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
KIRREL1	NM_018240.7	c.917-8C>A		splice_region_variant, intron_variant	Intron 7 of 14	ENST00000359209.11	NP_060710.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIRREL1	ENST00000359209.11	c.917-8C>A		splice_region_variant, intron_variant	Intron 7 of 14	1	NM_018240.7	ENSP00000352138.6
KIRREL1	ENST00000360089.8	c.425-8C>A		splice_region_variant, intron_variant	Intron 5 of 12	1		ENSP00000353202.4
KIRREL1	ENST00000368173.7	c.617-8C>A		splice_region_variant, intron_variant	Intron 5 of 12	2		ENSP00000357155.4
KIRREL1	ENST00000368172.2	c.563-8C>A		splice_region_variant, intron_variant	Intron 4 of 11	2		ENSP00000357154.2

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

GnomAD2 exomes AF: 0.533 AC: 131791 AN: 247138 AF XY: 0.536

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 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

African (AFR) AF: 0.0927 AC: 3082 AN: 33248

American (AMR) AF: 0.655 AC: 28823 AN: 43978

Ashkenazi Jewish (ASJ) AF: 0.390 AC: 10020 AN: 25722

East Asian (EAS) AF: 0.672 AC: 26646 AN: 39656

South Asian (SAS) AF: 0.581 AC: 49493 AN: 85250

European-Finnish (FIN) AF: 0.579 AC: 30858 AN: 53322

Middle Eastern (MID) AF: 0.385 AC: 2206 AN: 5736

European-Non Finnish (NFE) AF: 0.524 AC: 581154 AN: 1109206

Other (OTH) AF: 0.498 AC: 29939 AN: 60134

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

African (AFR) AF: 0.112 AC: 4643 AN: 41442

American (AMR) AF: 0.545 AC: 8309 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.382 AC: 1325 AN: 3468

East Asian (EAS) AF: 0.682 AC: 3492 AN: 5120

South Asian (SAS) AF: 0.589 AC: 2817 AN: 4786

European-Finnish (FIN) AF: 0.584 AC: 6153 AN: 10536

Middle Eastern (MID) AF: 0.373 AC: 109 AN: 292

European-Non Finnish (NFE) AF: 0.524 AC: 35559 AN: 67874

Other (OTH) AF: 0.423 AC: 890 AN: 2106

Alfa AF: 0.484 Hom.: 65541

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
PhyloP100		-0.34
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6427419; hg19: chr1-158058109;