11-126424926-G-T

Variant names:

• chr11-126424926-G-T
• rs200640353
• NM_032531.4:c.1991C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032531.4(KIRREL3):​c.1991C>A​(p.Ala664Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,450,418 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A664V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: KIRREL3 NM_032531.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.47
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09826797).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIRREL3	NM_032531.4	c.1991C>A	p.Ala664Glu	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.1991C>A	p.Ala664Glu	missense_variant	Exon 17 of 17	1	NM_032531.4	ENSP00000435466.2
KIRREL3	ENST00000529097.6	c.1955C>A	p.Ala652Glu	missense_variant	Exon 16 of 16	1		ENSP00000434081.2
ST3GAL4	ENST00000524834.5	n.630-15260G>T		intron_variant	Intron 6 of 6	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1450418 Hom.: 0 Cov.: 34 AF XY: 0.00000139 AC XY: 1 AN XY: 719304

African (AFR) AF: 0.00 AC: 0 AN: 33182

American (AMR) AF: 0.00 AC: 0 AN: 44278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25804

East Asian (EAS) AF: 0.00 AC: 0 AN: 39416

South Asian (SAS) AF: 0.00 AC: 0 AN: 85726

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53034

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5728

European-Non Finnish (NFE) AF: 9.06e-7 AC: 1 AN: 1103382

Other (OTH) AF: 0.00 AC: 0 AN: 59868

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.047	T;T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.82	T;T
M_CAP	Benign	0.0086	T
MetaRNN	Benign	0.098	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;.
PhyloP100		3.5
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.070
Sift	Benign	0.10	T;T
Sift4G	Benign	0.082	T;T
Polyphen		0.29	B;B
Vest4		0.17
MutPred		0.55		Gain of sheet (P = 0.0011);.;
MVP		0.093
MPC		0.57
ClinPred		0.22	T
GERP RS		4.0
Varity_R		0.13
gMVP		0.46
Mutation Taster		=82/18	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: rs200640353; hg19: chr11-126294821; COSMIC: COSV69384397; COSMIC: COSV69384397;