11-126431400-C-G

Variant names:

• chr11-126431400-C-G
• rs1555100391
• ENST00000525704.2:c.1715G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000525144.7(KIRREL3):​c.1696+19G>C variant causes a intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KIRREL3 ENST00000525144.7 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.60
• 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]

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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4076989).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000525144.7. 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.1696+19G>C		intron	N/A	NP_115920.1
	KIRREL3	NM_001441253.1		c.1715G>C	p.Gly572Ala	missense	Exon 14 of 17	NP_001428182.1
	KIRREL3	NM_001441251.1		c.1679G>C	p.Gly560Ala	missense	Exon 13 of 16	NP_001428180.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIRREL3	ENST00000525704.2	TSL:1	c.1715G>C	p.Gly572Ala	missense	Exon 14 of 14	ENSP00000435094.2
	KIRREL3	ENST00000525144.7	TSL:1 MANE Select	c.1696+19G>C		intron	N/A	ENSP00000435466.2
	KIRREL3	ENST00000529097.6	TSL:1	c.1660+19G>C		intron	N/A	ENSP00000434081.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Difficulty walking;C0557874:Global developmental delay;C1854882:Absent speech;C1857790:Thoracic scoliosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.021	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	21
DANN	Uncertain	1.0
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.37	T
M_CAP	Pathogenic	0.36	D
MetaRNN	Benign	0.41	T
MetaSVM	Uncertain	-0.23	T
PhyloP100		3.6
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.18
Sift	Benign	0.10	T
Sift4G	Benign	0.12	T
Polyphen		1.0	D
Vest4		0.43
MutPred		0.33		Loss of helix (P = 0.0123)
MVP		0.23
ClinPred		0.68	D
GERP RS		5.5
Mutation Taster		=68/32	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1555100391; hg19: chr11-126301295;