11-126562873-C-T

Position:

• chr11-126562873-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_032531.4(KIRREL3):​c.95G>A​(p.Gly32Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: KIRREL3 NM_032531.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.84

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-AS1 (HGNC:42655): (KIRREL3 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.858

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIRREL3	NM_032531.4	c.95G>A	p.Gly32Asp	missense_variant	2/17	ENST00000525144.7	NP_115920.1
KIRREL3-AS1	NR_174952.1	n.418+18629C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIRREL3	ENST00000525144.7	c.95G>A	p.Gly32Asp	missense_variant	2/17	1	NM_032531.4	ENSP00000435466	P4
KIRREL3-AS1	ENST00000548204.1	n.298+18629C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 15, 2024

The c.95G>A (p.G32D) alteration is located in exon 2 (coding exon 2) of the KIRREL3 gene. This alteration results from a G to A substitution at nucleotide position 95, causing the glycine (G) at amino acid position 32 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.056	T;T;.
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.86	D;D;D
M_CAP	Benign	0.060	D
MetaRNN	Pathogenic	0.86	D;D;D
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	0.0	N;.;N
MutationTaster	Benign	0.95	D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.1	N;N;N
REVEL	Uncertain	0.45
Sift	Uncertain	0.021	D;D;D
Sift4G	Benign	0.15	T;T;T
Polyphen		1.0	D;D;D
Vest4		0.87
MutPred		0.68		Gain of ubiquitination at K36 (P = 0.0594);Gain of ubiquitination at K36 (P = 0.0594);Gain of ubiquitination at K36 (P = 0.0594);
MVP		0.84
MPC		1.4
ClinPred		0.95	D
GERP RS		5.6
Varity_R		0.28
gMVP		0.90

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-126432768; COSMIC: COSV73107690;