11-126424650-T-A

Variant names:

• chr11-126424650-T-A
• rs368525135
• NM_032531.4:c.2267A>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032531.4(KIRREL3):​c.2267A>T​(p.His756Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000663 in 150,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: KIRREL3 NM_032531.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.45

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16698349).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIRREL3	NM_032531.4	c.2267A>T	p.His756Leu	missense_variant	Exon 17 of 17	ENST00000525144.7	NP_115920.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIRREL3	ENST00000525144.7	c.2267A>T	p.His756Leu	missense_variant	Exon 17 of 17	1	NM_032531.4	ENSP00000435466.2
KIRREL3	ENST00000529097.6	c.2231A>T	p.His744Leu	missense_variant	Exon 16 of 16	1		ENSP00000434081.2
ST3GAL4	ENST00000524834.5	n.629+15239T>A		intron_variant	Intron 6 of 6	2

Frequencies

GnomAD3 genomes AF: 0.00000663 AC: 1 AN: 150824 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000662

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000663 AC: 1 AN: 150824 Hom.: 0 Cov.: 33 AF XY: 0.0000136 AC XY: 1 AN XY: 73550

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000662

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.096	T
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.054	T;T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.046
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.11
Sift	Benign	0.066	T;T
Sift4G	Benign	0.63	T;T
Polyphen		0.075	B;B
Vest4		0.41
MutPred		0.23		Gain of loop (P = 0.0435);.;
MVP		0.10
MPC		0.59
ClinPred		0.89	D
GERP RS		4.6
Varity_R		0.20
gMVP		0.60

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

Publications

LitVar

Other links and lift over

dbSNP: rs368525135; hg19: chr11-126294545;