chr11-126778245-C-G

Variant names:

• chr11-126778245-C-G
• rs1946052
• NM_032531.4:c.56-215333G>C

Variant summary

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

The NM_032531.4(KIRREL3):​c.56-215333G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.592 in 152,000 control chromosomes in the GnomAD database, including 26,737 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 0.59 (26737 hom., cov: 32)
• Consequence: KIRREL3 NM_032531.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.178
• Publications: 3 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=-0.95).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.796 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIRREL3	NM_032531.4	c.56-215333G>C		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.56-215333G>C		intron_variant	Intron 1 of 16	1	NM_032531.4	ENSP00000435466.2

Frequencies

GnomAD3 genomes AF: 0.592 AC: 89849 AN: 151882 Hom.: 26724 Cov.: 32

Gnomad AFR AF: 0.627

Gnomad AMI AF: 0.487

Gnomad AMR AF: 0.579

Gnomad ASJ AF: 0.560

Gnomad EAS AF: 0.816

Gnomad SAS AF: 0.621

Gnomad FIN AF: 0.512

Gnomad MID AF: 0.576

Gnomad NFE AF: 0.569

Gnomad OTH AF: 0.596

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

GnomAD4 genome AF: 0.592 AC: 89914 AN: 152000 Hom.: 26737 Cov.: 32 AF XY: 0.591 AC XY: 43878 AN XY: 74292

African (AFR) AF: 0.627 AC: 25971 AN: 41430

American (AMR) AF: 0.580 AC: 8856 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.560 AC: 1940 AN: 3466

East Asian (EAS) AF: 0.816 AC: 4232 AN: 5184

South Asian (SAS) AF: 0.621 AC: 2986 AN: 4812

European-Finnish (FIN) AF: 0.512 AC: 5407 AN: 10558

Middle Eastern (MID) AF: 0.578 AC: 170 AN: 294

European-Non Finnish (NFE) AF: 0.569 AC: 38645 AN: 67958

Other (OTH) AF: 0.600 AC: 1263 AN: 2106

Alfa AF: 0.441 Hom.: 1152

Bravo AF: 0.599

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	1.7
DANN	Benign	0.48
PhyloP100		0.18
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: rs1946052; hg19: chr11-126648140;