11-126994692-G-T

Variant names:

• chr11-126994692-G-T
• rs541783
• NM_032531.4:c.55+5763C>A

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+5763C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.16 in 152,172 control chromosomes in the GnomAD database, including 2,305 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 0.16 (2305 hom., cov: 32)
• Consequence: KIRREL3 NM_032531.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.99
• Publications: 1 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

ENSG00000255317 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.237 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+5763C>A		intron	N/A	NP_115920.1
	KIRREL3	NM_001441252.1		c.55+5763C>A		intron	N/A	NP_001428181.1
	KIRREL3	NM_001441253.1		c.55+5763C>A		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+5763C>A		intron	N/A	ENSP00000435466.2
	KIRREL3	ENST00000529097.6	TSL:1	c.55+5763C>A		intron	N/A	ENSP00000434081.2
	KIRREL3	ENST00000525704.2	TSL:1	c.55+5763C>A		intron	N/A	ENSP00000435094.2

Frequencies

GnomAD3 genomes AF: 0.160 AC: 24403 AN: 152054 Hom.: 2306 Cov.: 32

Gnomad AFR AF: 0.241

Gnomad AMI AF: 0.184

Gnomad AMR AF: 0.124

Gnomad ASJ AF: 0.272

Gnomad EAS AF: 0.00308

Gnomad SAS AF: 0.121

Gnomad FIN AF: 0.0865

Gnomad MID AF: 0.296

Gnomad NFE AF: 0.139

Gnomad OTH AF: 0.174

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

GnomAD4 genome AF: 0.160 AC: 24417 AN: 152172 Hom.: 2305 Cov.: 32 AF XY: 0.157 AC XY: 11668 AN XY: 74394

African (AFR) AF: 0.241 AC: 10004 AN: 41482

American (AMR) AF: 0.123 AC: 1886 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.272 AC: 945 AN: 3470

East Asian (EAS) AF: 0.00309 AC: 16 AN: 5176

South Asian (SAS) AF: 0.120 AC: 579 AN: 4822

European-Finnish (FIN) AF: 0.0865 AC: 917 AN: 10606

Middle Eastern (MID) AF: 0.281 AC: 82 AN: 292

European-Non Finnish (NFE) AF: 0.139 AC: 9457 AN: 68006

Other (OTH) AF: 0.172 AC: 363 AN: 2114

Alfa AF: 0.155 Hom.: 5366

Bravo AF: 0.170

Asia WGS AF: 0.0620 AC: 215 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	8.3
DANN	Benign	0.79
PhyloP100		3.0
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: rs541783; hg19: chr11-126864588;