rs35152573

Variant names:

• chr11-126521352-G-A
• rs35152573
• NM_032531.4:c.396C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_032531.4(KIRREL3):​c.396C>T​(p.Ala132Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000969 in 1,553,852 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00064 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0010 (1 hom.)
• Consequence: KIRREL3 NM_032531.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 11-126521352-G-A is Benign according to our data. Variant chr11-126521352-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 211307.
• BP7: Synonymous conserved (PhyloP=-5.74 with no splicing effect.
• BS2: High AC in GnomAd4 at 98 AD,Unknown gene.

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>T	p.Ala132Ala	synonymous	Exon 4 of 17	NP_115920.1
	KIRREL3	NM_001441252.1		c.504C>T	p.Ala168Ala	synonymous	Exon 5 of 18	NP_001428181.1
	KIRREL3	NM_001441253.1		c.396C>T	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>T	p.Ala132Ala	synonymous	Exon 4 of 17	ENSP00000435466.2
	KIRREL3	ENST00000529097.6	TSL:1	c.396C>T	p.Ala132Ala	synonymous	Exon 4 of 16	ENSP00000434081.2
	KIRREL3	ENST00000525704.2	TSL:1	c.396C>T	p.Ala132Ala	synonymous	Exon 4 of 14	ENSP00000435094.2

Frequencies

GnomAD3 genomes AF: 0.000644 AC: 98 AN: 152200 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00122

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000566 AC: 90 AN: 158890 AF XY: 0.000486

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000161

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000179

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00128

Gnomad OTH exome AF: 0.000226

GnomAD4 exome AF: 0.00100 AC: 1408 AN: 1401652 Hom.: 1 Cov.: 31 AF XY: 0.000943 AC XY: 652 AN XY: 691630

African (AFR) AF: 0.000126 AC: 4 AN: 31696

American (AMR) AF: 0.000195 AC: 7 AN: 35984

Ashkenazi Jewish (ASJ) AF: 0.0000398 AC: 1 AN: 25154

East Asian (EAS) AF: 0.0000835 AC: 3 AN: 35916

South Asian (SAS) AF: 0.0000378 AC: 3 AN: 79370

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49230

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

European-Non Finnish (NFE) AF: 0.00125 AC: 1351 AN: 1080494

Other (OTH) AF: 0.000671 AC: 39 AN: 58118

GnomAD4 genome AF: 0.000644 AC: 98 AN: 152200 Hom.: 1 Cov.: 33 AF XY: 0.000632 AC XY: 47 AN XY: 74346

African (AFR) AF: 0.000265 AC: 11 AN: 41458

American (AMR) AF: 0.000131 AC: 2 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00122 AC: 83 AN: 68052

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.000950 Hom.: 0

Bravo AF: 0.000540

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	2.4
DANN	Benign	0.83
PhyloP100		-5.7
Mutation Taster		=100/0	polymorphism

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: rs35152573; hg19: chr11-126391247;