Genetic Variant NM_032531.4:c.95G>A (chr11-126562873-C-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_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

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.84

Publications

0 publications found

Variant links:

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 links:

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

KIRREL3-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.858

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KIRREL3	NM_032531.4	MANE Select	c.95G>A	p.Gly32Asp	missense	Exon 2 of 17	NP_115920.1	Q8IZU9-1
KIRREL3	NM_001441252.1		c.95G>A	p.Gly32Asp	missense	Exon 2 of 18	NP_001428181.1
KIRREL3	NM_001441253.1		c.95G>A	p.Gly32Asp	missense	Exon 2 of 17	NP_001428182.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KIRREL3	ENST00000525144.7	TSL:1 MANE Select	c.95G>A	p.Gly32Asp	missense	Exon 2 of 17	ENSP00000435466.2	Q8IZU9-1
KIRREL3	ENST00000529097.6	TSL:1	c.95G>A	p.Gly32Asp	missense	Exon 2 of 16	ENSP00000434081.2	E9PRX9
KIRREL3	ENST00000525704.2	TSL:1	c.95G>A	p.Gly32Asp	missense	Exon 2 of 14	ENSP00000435094.2	Q8IZU9-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.54

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.17

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.056

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.86

M_CAP

Benign

0.060

MetaRNN

Pathogenic

0.86

MetaSVM

Benign

-0.52

MutationAssessor

Benign

0.0

PhyloP100

4.8

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-1.1

REVEL

Uncertain

0.45

Sift

Uncertain

0.021

Sift4G

Benign

0.15

Polyphen

1.0

Vest4

0.87

MutPred

0.68

Gain of ubiquitination at K36 (P = 0.0594)

MVP

0.84

MPC

1.4

ClinPred

0.95

GERP RS

5.6

Varity_R

0.28

gMVP

0.90

Mutation Taster

=42/58

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over