11-126994498-G-T

Variant names:

• chr11-126994498-G-T
• rs488054
• NM_032531.4:c.55+5957C>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_032531.4(KIRREL3):​c.55+5957C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.204 in 152,178 control chromosomes in the GnomAD database, including 3,872 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 0.20 (3872 hom., cov: 32)
• Consequence: KIRREL3 NM_032531.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.72
• 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: AD, Unknown Classification: LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• complex neurodevelopmental disorder

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000255317 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.332 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIRREL3	NM_032531.4	MANE Select	c.55+5957C>A		intron	N/A	NP_115920.1	Q8IZU9-1
	KIRREL3	NM_001441252.1		c.55+5957C>A		intron	N/A	NP_001428181.1
	KIRREL3	NM_001441253.1		c.55+5957C>A		intron	N/A	NP_001428182.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIRREL3	ENST00000525144.7	TSL:1 MANE Select	c.55+5957C>A		intron	N/A	ENSP00000435466.2	Q8IZU9-1
	KIRREL3	ENST00000529097.6	TSL:1	c.55+5957C>A		intron	N/A	ENSP00000434081.2	E9PRX9
	KIRREL3	ENST00000525704.2	TSL:1	c.55+5957C>A		intron	N/A	ENSP00000435094.2	Q8IZU9-2

Frequencies

GnomAD3 genomes AF: 0.204 AC: 31063 AN: 152060 Hom.: 3871 Cov.: 32

Gnomad AFR AF: 0.337

Gnomad AMI AF: 0.208

Gnomad AMR AF: 0.157

Gnomad ASJ AF: 0.286

Gnomad EAS AF: 0.00346

Gnomad SAS AF: 0.126

Gnomad FIN AF: 0.0970

Gnomad MID AF: 0.323

Gnomad NFE AF: 0.166

Gnomad OTH AF: 0.223

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

GnomAD4 genome AF: 0.204 AC: 31079 AN: 152178 Hom.: 3872 Cov.: 32 AF XY: 0.197 AC XY: 14684 AN XY: 74412

African (AFR) AF: 0.337 AC: 13971 AN: 41468

American (AMR) AF: 0.157 AC: 2398 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.286 AC: 991 AN: 3468

East Asian (EAS) AF: 0.00347 AC: 18 AN: 5186

South Asian (SAS) AF: 0.126 AC: 608 AN: 4828

European-Finnish (FIN) AF: 0.0970 AC: 1027 AN: 10592

Middle Eastern (MID) AF: 0.306 AC: 90 AN: 294

European-Non Finnish (NFE) AF: 0.166 AC: 11322 AN: 68022

Other (OTH) AF: 0.220 AC: 465 AN: 2110

Alfa AF: 0.118 Hom.: 303

Bravo AF: 0.219

Asia WGS AF: 0.0700 AC: 245 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	15
DANN	Benign	0.83
PhyloP100		1.7
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: rs488054; hg19: chr11-126864394;