11-126424922-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_032531.4(KIRREL3):c.1995C>T(p.Gly665=) variant causes a synonymous change. The variant allele was found at a frequency of 0.636 in 1,604,440 control chromosomes in the GnomAD database, including 327,436 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.67 (34316 hom., cov: 35)
  • Exomes 𝑓: 0.63 (293120 hom.)
• Consequence: KIRREL3 NM_032531.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 4.21

Genes affected

KIRREL3 (HGNC:23204): (kirre like nephrin family adhesion molecule 3) The protein encoded by this gene is a member of the nephrin-like protein family. These proteins are expressed in fetal and adult brain, and also in podocytes of kidney glomeruli. The cytoplasmic domains of these proteins interact with the C-terminus of podocin, also expressed in the podocytes, cells involved in ensuring size- and charge-selective ultrafiltration. The protein encoded by this gene is a synaptic cell adhesion molecule with multiple extracellular immunoglobulin-like domains and a cytoplasmic PDZ domain-binding motif. Mutations in this gene are associated with several neurological and cognitive disorders. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2017]

ST3GAL4 (HGNC:10864): (ST3 beta-galactoside alpha-2,3-sialyltransferase 4) This gene encodes a member of the glycosyltransferase 29 family, a group of enzymes involved in protein glycosylation. The encoded protein is targeted to Golgi membranes but may be proteolytically processed and secreted. The gene product may also be involved in the increased expression of sialyl Lewis X antigen seen in inflammatory responses. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 11-126424922-G-A is Benign according to our data. Variant chr11-126424922-G-A is described in ClinVar as [Benign]. Clinvar id is 129425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-126424922-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.884 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIRREL3	NM_032531.4	c.1995C>T	p.Gly665=	synonymous_variant	17/17	ENST00000525144.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIRREL3	ENST00000525144.7	c.1995C>T	p.Gly665=	synonymous_variant	17/17	1	NM_032531.4	P4
KIRREL3	ENST00000529097.6	c.1959C>T	p.Gly653=	synonymous_variant	16/16	1		A1
ST3GAL4	ENST00000524834.5	n.630-15264G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.668 AC: 101646 AN: 152066 Hom.: 34299 Cov.: 35

Gnomad AFR AF: 0.719

Gnomad AMI AF: 0.563

Gnomad AMR AF: 0.627

Gnomad ASJ AF: 0.781

Gnomad EAS AF: 0.906

Gnomad SAS AF: 0.649

Gnomad FIN AF: 0.647

Gnomad MID AF: 0.614

Gnomad NFE AF: 0.629

Gnomad OTH AF: 0.677

GnomAD3 exomes AF: 0.661 AC: 162630 AN: 245874 Hom.: 54549 AF XY: 0.660 AC XY: 88068 AN XY: 133458

Gnomad AFR exome AF: 0.720

Gnomad AMR exome AF: 0.591

Gnomad ASJ exome AF: 0.779

Gnomad EAS exome AF: 0.908

Gnomad SAS exome AF: 0.643

Gnomad FIN exome AF: 0.645

Gnomad NFE exome AF: 0.633

Gnomad OTH exome AF: 0.664

GnomAD4 exome AF: 0.633 AC: 919027 AN: 1452256 Hom.: 293120 Cov.: 64 AF XY: 0.634 AC XY: 456527 AN XY: 720542

Gnomad4 AFR exome AF: 0.724

Gnomad4 AMR exome AF: 0.590

Gnomad4 ASJ exome AF: 0.776

Gnomad4 EAS exome AF: 0.889

Gnomad4 SAS exome AF: 0.647

Gnomad4 FIN exome AF: 0.645

Gnomad4 NFE exome AF: 0.616

Gnomad4 OTH exome AF: 0.648

GnomAD4 genome AF: 0.668 AC: 101714 AN: 152184 Hom.: 34316 Cov.: 35 AF XY: 0.671 AC XY: 49937 AN XY: 74394

Gnomad4 AFR AF: 0.719

Gnomad4 AMR AF: 0.627

Gnomad4 ASJ AF: 0.781

Gnomad4 EAS AF: 0.906

Gnomad4 SAS AF: 0.649

Gnomad4 FIN AF: 0.647

Gnomad4 NFE AF: 0.629

Gnomad4 OTH AF: 0.678

Alfa AF: 0.650 Hom.: 18185

Bravo AF: 0.668

Asia WGS AF: 0.730 AC: 2539 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

-

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 22, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
Cadd	Benign	9.7
Dann	Benign	0.82

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs948052; hg19: chr11-126294817; COSMIC: COSV69386762; COSMIC: COSV69386762;