11-126939809-T-C

Variant names:

• chr11-126939809-T-C
• rs1939992
• NM_032531.4:c.55+60646A>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+60646A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.793 in 152,110 control chromosomes in the GnomAD database, including 48,018 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 0.79 (48018 hom., cov: 31)
• Consequence: KIRREL3 NM_032531.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.645
• Publications: 10 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

ENSG00000254938 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.816 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIRREL3	NM_032531.4	c.55+60646A>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+60646A>G		intron_variant	Intron 1 of 16	1	NM_032531.4	ENSP00000435466.2

Frequencies

GnomAD3 genomes AF: 0.793 AC: 120554 AN: 151992 Hom.: 47968 Cov.: 31

Gnomad AFR AF: 0.824

Gnomad AMI AF: 0.788

Gnomad AMR AF: 0.819

Gnomad ASJ AF: 0.660

Gnomad EAS AF: 0.794

Gnomad SAS AF: 0.825

Gnomad FIN AF: 0.825

Gnomad MID AF: 0.766

Gnomad NFE AF: 0.769

Gnomad OTH AF: 0.765

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

GnomAD4 genome AF: 0.793 AC: 120660 AN: 152110 Hom.: 48018 Cov.: 31 AF XY: 0.797 AC XY: 59274 AN XY: 74362

African (AFR) AF: 0.823 AC: 34154 AN: 41486

American (AMR) AF: 0.820 AC: 12533 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.660 AC: 2291 AN: 3470

East Asian (EAS) AF: 0.794 AC: 4100 AN: 5166

South Asian (SAS) AF: 0.827 AC: 3980 AN: 4814

European-Finnish (FIN) AF: 0.825 AC: 8726 AN: 10576

Middle Eastern (MID) AF: 0.782 AC: 230 AN: 294

European-Non Finnish (NFE) AF: 0.769 AC: 52304 AN: 67992

Other (OTH) AF: 0.768 AC: 1623 AN: 2112

Alfa AF: 0.769 Hom.: 150470

Bravo AF: 0.790

Asia WGS AF: 0.845 AC: 2937 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.28
DANN	Benign	0.55
PhyloP100		-0.65
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: rs1939992; hg19: chr11-126809705;