chr11-126449098-A-G

Position:

• chr11-126449098-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_032531.4(KIRREL3):​c.908T>C​(p.Val303Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00089 in 1,613,672 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00053 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00093 (0 hom.)
• Consequence: KIRREL3 NM_032531.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts U:2 B:2
• Conservation: PhyloP100: 4.10

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12330669).
• BP6: Variant 11-126449098-A-G is Benign according to our data. Variant chr11-126449098-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 129429.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 81 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIRREL3	NM_032531.4	c.908T>C	p.Val303Ala	missense_variant	8/17	ENST00000525144.7	NP_115920.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIRREL3	ENST00000525144.7	c.908T>C	p.Val303Ala	missense_variant	8/17	1	NM_032531.4	ENSP00000435466.2
KIRREL3	ENST00000529097.6	c.908T>C	p.Val303Ala	missense_variant	8/16	1		ENSP00000434081.2
KIRREL3	ENST00000525704.2	c.908T>C	p.Val303Ala	missense_variant	8/14	1		ENSP00000435094.2

Frequencies

GnomAD3 genomes AF: 0.000533 AC: 81 AN: 152036 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00100

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000421 AC: 105 AN: 249232 Hom.: 0 AF XY: 0.000481 AC XY: 65 AN XY: 135208

Gnomad AFR exome AF: 0.000387

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.000795

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000752

Gnomad OTH exome AF: 0.000496

GnomAD4 exome AF: 0.000927 AC: 1355 AN: 1461636 Hom.: 0 Cov.: 31 AF XY: 0.000924 AC XY: 672 AN XY: 727094

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.00115

Gnomad4 OTH exome AF: 0.000514

GnomAD4 genome AF: 0.000533 AC: 81 AN: 152036 Hom.: 1 Cov.: 33 AF XY: 0.000498 AC XY: 37 AN XY: 74244

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.00100

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.00102 Hom.: 0

Bravo AF: 0.000457

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000238 AC: 1

ESP6500EA AF: 0.000593 AC: 5

ExAC AF: 0.000306 AC: 37

EpiCase AF: 0.000709

EpiControl AF: 0.000415

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 29, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.054	T;T;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.78	T;T;T
M_CAP	Benign	0.0081	T
MetaRNN	Benign	0.12	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.82	L;.;L
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.49	N;N;N
REVEL	Benign	0.15
Sift	Benign	0.64	T;T;T
Sift4G	Benign	0.36	T;T;T
Polyphen		0.94	P;D;D
Vest4		0.32
MVP		0.31
MPC		1.4
ClinPred		0.049	T
GERP RS		5.3
Varity_R		0.11
gMVP		0.68

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: rs201725914; hg19: chr11-126318993;