11-126423390-A-T

Variant names:

• chr11-126423390-A-T
• rs752805
• NM_032531.4:c.*1190T>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.*1190T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.577 in 151,956 control chromosomes in the GnomAD database, including 25,842 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 0.58 (25841 hom., cov: 32)
  • Exomes 𝑓: 0.42 (1 hom.)
• Consequence: KIRREL3 NM_032531.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.874
• Publications: 6 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]

ST3GAL4 (HGNC:10864): (ST3 beta-galactoside alpha-2,3-sialyltransferase 4) This gene encodes a member of the glycosyltransferase 29 family, a group of enzymes involved in protein glycosylation. The encoded protein is targeted to Golgi membranes but may be proteolytically processed and secreted. The gene product may also be involved in the increased expression of sialyl Lewis X antigen seen in inflammatory responses. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.872 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.*1190T>A		3_prime_UTR	Exon 17 of 17	NP_115920.1	Q8IZU9-1
	KIRREL3	NM_001441252.1		c.*1190T>A		3_prime_UTR	Exon 18 of 18	NP_001428181.1
	KIRREL3	NM_001441253.1		c.*1190T>A		3_prime_UTR	Exon 17 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.*1190T>A		3_prime_UTR	Exon 17 of 17	ENSP00000435466.2	Q8IZU9-1
	ST3GAL4	ENST00000524834.5	TSL:2	n.629+13979A>T		intron	N/A
	KIRREL3	ENST00000529097.6	TSL:1	c.*1190T>A		downstream_gene	N/A	ENSP00000434081.2	E9PRX9

Frequencies

GnomAD3 genomes AF: 0.577 AC: 87568 AN: 151822 Hom.: 25798 Cov.: 32

Gnomad AFR AF: 0.662

Gnomad AMI AF: 0.367

Gnomad AMR AF: 0.555

Gnomad ASJ AF: 0.584

Gnomad EAS AF: 0.893

Gnomad SAS AF: 0.476

Gnomad FIN AF: 0.495

Gnomad MID AF: 0.487

Gnomad NFE AF: 0.528

Gnomad OTH AF: 0.579

GnomAD4 exome AF: 0.417 AC: 5 AN: 12 Hom.: 1 Cov.: 0 AF XY: 0.400 AC XY: 4 AN XY: 10

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.500 AC: 4 AN: 8

Other (OTH) AF: 0.500 AC: 1 AN: 2

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0225104), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.577 AC: 87671 AN: 151944 Hom.: 25841 Cov.: 32 AF XY: 0.576 AC XY: 42795 AN XY: 74254

African (AFR) AF: 0.662 AC: 27422 AN: 41396

American (AMR) AF: 0.555 AC: 8470 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.584 AC: 2027 AN: 3472

East Asian (EAS) AF: 0.894 AC: 4620 AN: 5170

South Asian (SAS) AF: 0.475 AC: 2287 AN: 4812

European-Finnish (FIN) AF: 0.495 AC: 5226 AN: 10550

Middle Eastern (MID) AF: 0.503 AC: 148 AN: 294

European-Non Finnish (NFE) AF: 0.528 AC: 35913 AN: 67958

Other (OTH) AF: 0.579 AC: 1224 AN: 2114

Alfa AF: 0.443 Hom.: 1283

Bravo AF: 0.589

Asia WGS AF: 0.639 AC: 2224 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.77
DANN	Benign	0.78
PhyloP100		-0.87
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: rs752805; hg19: chr11-126293285;