11-126562852-A-T

Position:

• chr11-126562852-A-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_032531.4(KIRREL3):​c.116T>A​(p.Phe39Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00177 in 1,613,718 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (2 hom.)
• Consequence: KIRREL3 NM_032531.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.84

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.021294415).
• BP6: Variant 11-126562852-A-T is Benign according to our data. Variant chr11-126562852-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 129420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 169 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIRREL3	NM_032531.4	c.116T>A	p.Phe39Tyr	missense_variant	2/17	ENST00000525144.7	NP_115920.1
KIRREL3-AS1	NR_174952.1	n.418+18608A>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIRREL3	ENST00000525144.7	c.116T>A	p.Phe39Tyr	missense_variant	2/17	1	NM_032531.4	ENSP00000435466	P4
KIRREL3-AS1	ENST00000548204.1	n.298+18608A>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00111 AC: 169 AN: 152048 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00216

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000895 AC: 223 AN: 249118 Hom.: 0 AF XY: 0.000888 AC XY: 120 AN XY: 135142

Gnomad AFR exome AF: 0.000323

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.000497

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00177

Gnomad OTH exome AF: 0.000496

GnomAD4 exome AF: 0.00184 AC: 2695 AN: 1461552 Hom.: 2 Cov.: 31 AF XY: 0.00173 AC XY: 1256 AN XY: 727046

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000318

Gnomad4 NFE exome AF: 0.00227

Gnomad4 OTH exome AF: 0.00209

GnomAD4 genome AF: 0.00111 AC: 169 AN: 152166 Hom.: 0 Cov.: 32 AF XY: 0.000954 AC XY: 71 AN XY: 74394

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.00216

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.00172 Hom.: 0

Bravo AF: 0.00113

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00205 AC: 17

ExAC AF: 0.00102 AC: 123

EpiCase AF: 0.00196

EpiControl AF: 0.00160

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 19, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2022	KIRREL3: BS1, BS2 -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Dec 30, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Benign	0.033	T;T;.
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.084
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.67	T;T;T
M_CAP	Benign	0.0061	T
MetaRNN	Benign	0.021	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.0	N;.;N
MutationTaster	Benign	0.99	N;N;N
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.32	N;N;N
REVEL	Benign	0.081
Sift	Benign	0.19	T;T;T
Sift4G	Benign	0.35	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.42
MVP		0.33
MPC		0.48
ClinPred		0.018	T
GERP RS		5.5
Varity_R		0.082
gMVP		0.63

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: rs201204758; hg19: chr11-126432747;