11-126521352-G-T

Variant names:

• chr11-126521352-G-T
• NM_032531.4:c.396C>A
• KIRREL3 p.Ala132Ala

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_032531.4(KIRREL3):​c.396C>A​(p.Ala132Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. A132A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KIRREL3 NM_032531.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -5.74
• Publications: 0 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP7: Synonymous conserved (PhyloP=-5.74 with no splicing effect.

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.396C>A	p.Ala132Ala	synonymous	Exon 4 of 17	NP_115920.1	Q8IZU9-1
	KIRREL3	NM_001441252.1		c.504C>A	p.Ala168Ala	synonymous	Exon 5 of 18	NP_001428181.1
	KIRREL3	NM_001441253.1		c.396C>A	p.Ala132Ala	synonymous	Exon 4 of 17	NP_001428182.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIRREL3	ENST00000525144.7	TSL:1 MANE Select	c.396C>A	p.Ala132Ala	synonymous	Exon 4 of 17	ENSP00000435466.2	Q8IZU9-1
	KIRREL3	ENST00000529097.6	TSL:1	c.396C>A	p.Ala132Ala	synonymous	Exon 4 of 16	ENSP00000434081.2	E9PRX9
	KIRREL3	ENST00000525704.2	TSL:1	c.396C>A	p.Ala132Ala	synonymous	Exon 4 of 14	ENSP00000435094.2	Q8IZU9-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1401660 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 691632

African (AFR) AF: 0.00 AC: 0 AN: 31696

American (AMR) AF: 0.00 AC: 0 AN: 35984

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25154

East Asian (EAS) AF: 0.00 AC: 0 AN: 35916

South Asian (SAS) AF: 0.00 AC: 0 AN: 79370

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49234

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5690

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1080498

Other (OTH) AF: 0.00 AC: 0 AN: 58118

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.31
DANN	Benign	0.81
PhyloP100		-5.7

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr11-126391247;