11-127000522-C-T

Variant names:

• chr11-127000522-C-T
• rs3802824
• ENST00000533026.6:n.554G>A

Variant summary

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

The ENST00000533026.6(KIRREL3):​n.554G>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0467 in 1,600,170 control chromosomes in the GnomAD database, including 5,187 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 0.080 (1050 hom., cov: 32)
  • Exomes 𝑓: 0.043 (4137 hom.)
• Consequence: KIRREL3 ENST00000533026.6 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.189
• Publications: 13 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=-0.56).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.404 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000533026.6. 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.-13G>A		5_prime_UTR	Exon 1 of 17	NP_115920.1
	KIRREL3	NM_001441252.1		c.-13G>A		5_prime_UTR	Exon 1 of 18	NP_001428181.1
	KIRREL3	NM_001441253.1		c.-13G>A		5_prime_UTR	Exon 1 of 17	NP_001428182.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIRREL3	ENST00000533026.6	TSL:1	n.554G>A		non_coding_transcript_exon	Exon 2 of 4
	KIRREL3	ENST00000549874.1	TSL:1	n.249G>A		non_coding_transcript_exon	Exon 1 of 3
	KIRREL3	ENST00000525144.7	TSL:1 MANE Select	c.-13G>A		5_prime_UTR	Exon 1 of 17	ENSP00000435466.2

Frequencies

GnomAD3 genomes AF: 0.0798 AC: 12129 AN: 152052 Hom.: 1044 Cov.: 32

Gnomad AFR AF: 0.149

Gnomad AMI AF: 0.0636

Gnomad AMR AF: 0.0598

Gnomad ASJ AF: 0.0337

Gnomad EAS AF: 0.419

Gnomad SAS AF: 0.0777

Gnomad FIN AF: 0.0254

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.0280

Gnomad OTH AF: 0.0751

GnomAD2 exomes AF: 0.0706 AC: 15804 AN: 223834 AF XY: 0.0672

Gnomad AFR exome AF: 0.146

Gnomad AMR exome AF: 0.0491

Gnomad ASJ exome AF: 0.0298

Gnomad EAS exome AF: 0.429

Gnomad FIN exome AF: 0.0272

Gnomad NFE exome AF: 0.0282

Gnomad OTH exome AF: 0.0510

GnomAD4 exome AF: 0.0433 AC: 62651 AN: 1448000 Hom.: 4137 Cov.: 31 AF XY: 0.0434 AC XY: 31223 AN XY: 718700

African (AFR) AF: 0.150 AC: 4959 AN: 33148

American (AMR) AF: 0.0515 AC: 2214 AN: 43026

Ashkenazi Jewish (ASJ) AF: 0.0298 AC: 772 AN: 25880

East Asian (EAS) AF: 0.364 AC: 14103 AN: 38708

South Asian (SAS) AF: 0.0620 AC: 5173 AN: 83418

European-Finnish (FIN) AF: 0.0299 AC: 1570 AN: 52574

Middle Eastern (MID) AF: 0.0229 AC: 132 AN: 5756

European-Non Finnish (NFE) AF: 0.0270 AC: 29805 AN: 1105572

Other (OTH) AF: 0.0655 AC: 3923 AN: 59918

GnomAD4 genome AF: 0.0799 AC: 12156 AN: 152170 Hom.: 1050 Cov.: 32 AF XY: 0.0812 AC XY: 6039 AN XY: 74402

African (AFR) AF: 0.149 AC: 6196 AN: 41526

American (AMR) AF: 0.0597 AC: 913 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0337 AC: 117 AN: 3472

East Asian (EAS) AF: 0.419 AC: 2157 AN: 5150

South Asian (SAS) AF: 0.0774 AC: 371 AN: 4794

European-Finnish (FIN) AF: 0.0254 AC: 269 AN: 10610

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.0280 AC: 1902 AN: 68016

Other (OTH) AF: 0.0810 AC: 171 AN: 2112

Alfa AF: 0.0426 Hom.: 196

Bravo AF: 0.0873

Asia WGS AF: 0.226 AC: 782 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	13
DANN	Benign	0.90
PhyloP100		-0.19
PromoterAI		-0.018	Neutral
Mutation Taster		=293/7	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: rs3802824; hg19: chr11-126870418; COSMIC: COSV68778192; COSMIC: COSV68778192;