chr11-126884619-G-A

Variant names:

• chr11-126884619-G-A
• rs1940006
• NM_032531.4:c.55+115836C>T

Variant summary

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

The NM_032531.4(KIRREL3):​c.55+115836C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.617 in 152,080 control chromosomes in the GnomAD database, including 30,455 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.62 (30455 hom., cov: 33)
• Consequence: KIRREL3 NM_032531.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.01
• Publications: 5 publications found

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]

KIRREL3 Gene-Disease associations (from GenCC):

• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• intellectual disability, autosomal dominant 4

  Inheritance: Unknown, AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P
• complex neurodevelopmental disorder

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

LOC105369559 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.815 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032531.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIRREL3	NM_032531.4	MANE Select	c.55+115836C>T		intron	N/A	NP_115920.1
	KIRREL3	NM_001441252.1		c.55+115836C>T		intron	N/A	NP_001428181.1
	KIRREL3	NM_001441253.1		c.55+115836C>T		intron	N/A	NP_001428182.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIRREL3	ENST00000525144.7	TSL:1 MANE Select	c.55+115836C>T		intron	N/A	ENSP00000435466.2
	KIRREL3	ENST00000529097.6	TSL:1	c.55+115836C>T		intron	N/A	ENSP00000434081.2
	KIRREL3	ENST00000525704.2	TSL:1	c.55+115836C>T		intron	N/A	ENSP00000435094.2

Frequencies

GnomAD3 genomes AF: 0.617 AC: 93687 AN: 151962 Hom.: 30404 Cov.: 33

Gnomad AFR AF: 0.822

Gnomad AMI AF: 0.450

Gnomad AMR AF: 0.638

Gnomad ASJ AF: 0.465

Gnomad EAS AF: 0.699

Gnomad SAS AF: 0.626

Gnomad FIN AF: 0.506

Gnomad MID AF: 0.605

Gnomad NFE AF: 0.507

Gnomad OTH AF: 0.600

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.617 AC: 93797 AN: 152080 Hom.: 30455 Cov.: 33 AF XY: 0.619 AC XY: 45994 AN XY: 74344

African (AFR) AF: 0.822 AC: 34148 AN: 41526

American (AMR) AF: 0.638 AC: 9761 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.465 AC: 1614 AN: 3470

East Asian (EAS) AF: 0.699 AC: 3597 AN: 5148

South Asian (SAS) AF: 0.626 AC: 3018 AN: 4822

European-Finnish (FIN) AF: 0.506 AC: 5346 AN: 10556

Middle Eastern (MID) AF: 0.610 AC: 178 AN: 292

European-Non Finnish (NFE) AF: 0.507 AC: 34449 AN: 67950

Other (OTH) AF: 0.604 AC: 1276 AN: 2114

Alfa AF: 0.540 Hom.: 11703

Bravo AF: 0.636

Asia WGS AF: 0.695 AC: 2418 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.39
DANN	Benign	0.73
PhyloP100		-1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1940006; hg19: chr11-126754515;