chr11-126424650-T-G

Variant names:

• chr11-126424650-T-G
• rs368525135
• NM_032531.4:c.2267A>C

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.2267A>C​(p.His756Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,694 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. H756R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: KIRREL3 NM_032531.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.45
• 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=0.25169444).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIRREL3	NM_032531.4	MANE Select	c.2267A>C	p.His756Pro	missense	Exon 17 of 17	NP_115920.1	Q8IZU9-1
	KIRREL3	NM_001441252.1		c.2375A>C	p.His792Pro	missense	Exon 18 of 18	NP_001428181.1
	KIRREL3	NM_001441253.1		c.2342A>C	p.His781Pro	missense	Exon 17 of 17	NP_001428182.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIRREL3	ENST00000525144.7	TSL:1 MANE Select	c.2267A>C	p.His756Pro	missense	Exon 17 of 17	ENSP00000435466.2	Q8IZU9-1
	KIRREL3	ENST00000529097.6	TSL:1	c.2231A>C	p.His744Pro	missense	Exon 16 of 16	ENSP00000434081.2	E9PRX9
	ST3GAL4	ENST00000524834.5	TSL:2	n.629+15239T>G		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461694 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727124

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111866

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.081	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.033	T
Eigen	Benign	0.11
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		7.4
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.67	N
REVEL	Benign	0.13
Sift	Uncertain	0.022	D
Sift4G	Benign	0.21	T
Polyphen		0.89	P
Vest4		0.42
MutPred		0.24		Gain of glycosylation at H756 (P = 0.0092)
MVP		0.093
MPC		1.2
ClinPred		0.92	D
GERP RS		4.6
Varity_R		0.19
gMVP		0.62
Mutation Taster		=40/60	disease causing

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: rs368525135; hg19: chr11-126294545;