chr11-126982542-A-C

Variant names:

• chr11-126982542-A-C
• rs631562
• NM_032531.4:c.55+17913T>G

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+17913T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.527 in 152,056 control chromosomes in the GnomAD database, including 22,033 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 0.53 (22033 hom., cov: 33)
• Consequence: KIRREL3 NM_032531.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.995
• Publications: 2 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.813 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIRREL3	NM_032531.4	c.55+17913T>G		intron_variant	Intron 1 of 16	ENST00000525144.7	NP_115920.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIRREL3	ENST00000525144.7	c.55+17913T>G		intron_variant	Intron 1 of 16	1	NM_032531.4	ENSP00000435466.2

Frequencies

GnomAD3 genomes AF: 0.527 AC: 80095 AN: 151938 Hom.: 22007 Cov.: 33

Gnomad AFR AF: 0.648

Gnomad AMI AF: 0.621

Gnomad AMR AF: 0.482

Gnomad ASJ AF: 0.517

Gnomad EAS AF: 0.834

Gnomad SAS AF: 0.479

Gnomad FIN AF: 0.504

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.448

Gnomad OTH AF: 0.494

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

GnomAD4 genome AF: 0.527 AC: 80168 AN: 152056 Hom.: 22033 Cov.: 33 AF XY: 0.531 AC XY: 39485 AN XY: 74334

African (AFR) AF: 0.648 AC: 26870 AN: 41472

American (AMR) AF: 0.482 AC: 7361 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.517 AC: 1792 AN: 3468

East Asian (EAS) AF: 0.834 AC: 4311 AN: 5172

South Asian (SAS) AF: 0.477 AC: 2297 AN: 4814

European-Finnish (FIN) AF: 0.504 AC: 5331 AN: 10570

Middle Eastern (MID) AF: 0.425 AC: 125 AN: 294

European-Non Finnish (NFE) AF: 0.448 AC: 30470 AN: 67966

Other (OTH) AF: 0.497 AC: 1046 AN: 2106

Alfa AF: 0.476 Hom.: 76350

Bravo AF: 0.535

Asia WGS AF: 0.627 AC: 2179 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.83
DANN	Benign	0.37
PhyloP100		-0.99
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: rs631562; hg19: chr11-126852438;