rs79471015

Variant names:

• chr7-103833594-G-A
• NM_005045.4:c.416C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-103833594-G-A
• chr7-103833594-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005045.4(RELN):​c.416C>T​(p.Thr139Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RELN NM_005045.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.70

Genes affected

RELN (HGNC:9957): (reelin) This gene encodes a large secreted extracellular matrix protein thought to control cell-cell interactions critical for cell positioning and neuronal migration during brain development. This protein may be involved in schizophrenia, autism, bipolar disorder, major depression and in migration defects associated with temporal lobe epilepsy. Mutations of this gene are associated with autosomal recessive lissencephaly with cerebellar hypoplasia. Two transcript variants encoding distinct isoforms have been identified for this gene. Other transcript variants have been described but their full length nature has not been determined. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RELN	NM_005045.4	c.416C>T	p.Thr139Ile	missense_variant	Exon 3 of 65	ENST00000428762.6	NP_005036.2
RELN	NM_173054.3	c.416C>T	p.Thr139Ile	missense_variant	Exon 3 of 64		NP_774959.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RELN	ENST00000428762.6	c.416C>T	p.Thr139Ile	missense_variant	Exon 3 of 65	5	NM_005045.4	ENSP00000392423.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Norman-Roberts syndrome;C4225327:Familial temporal lobe epilepsy 7 Uncertain:1

May 08, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 139 of the RELN protein (p.Thr139Ile). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with RELN-related conditions. This variant is not present in population databases (gnomAD no frequency). -

Norman-Roberts syndrome Uncertain:1

Dec 27, 2022

Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence variant is a single nucleotide substitution (C>T) at coding position 416 of the RELN gene that results in a threonine to isoleucine amino acid change at residue 139 of the RELN protein product, Reelin. This is a novel variant that has not been reported to databases of clinically annotated variants, or observed in the literature in individuals with RELN-related illness, to our knowledge. This variant is also not observed in the gnomAD population database (0 of ~250,000 alleles). Multiple bioinformatic tools predict that this variant would be damaging, and the Thr139 residue is well conserved across the vertebrate species examined. Functiol studies testing the effect of this variant on protein structure or activity have not been performed, to our knowledge. At this time, there is insufficient evidence to determine if this variant is pathogenic or benign. Therefore, we consider this to be a variant of uncertain significance. ACMG Criteria: PM2, PP3 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Benign	-0.045	T
BayesDel_noAF	Benign	-0.30
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.097	T;.;.
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.86	D;D;D
M_CAP	Benign	0.015	T
MetaRNN	Uncertain	0.71	D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L;L;.
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-2.1	N;N;N
REVEL	Benign	0.26
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.0080	D;D;D
Polyphen		0.98	D;D;.
Vest4		0.82
MutPred		0.61		Loss of catalytic residue at T139 (P = 0.0025);Loss of catalytic residue at T139 (P = 0.0025);Loss of catalytic residue at T139 (P = 0.0025);
MVP		0.28
MPC		0.45
ClinPred		0.94	D
GERP RS		5.3
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.31
gMVP		0.56

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: chr7-103474041;