rs1554389059

chr7-103603428-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_005045.4(RELN):c.3209T>C(p.Met1070Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1070I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RELN NM_005045.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.69

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
• PP2: Missense variant where missense usually causes diseases, RELN
• BP4: Computational evidence support a benign effect (MetaRNN=0.37838697).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RELN	NM_005045.4	c.3209T>C	p.Met1070Thr	missense_variant	24/65	ENST00000428762.6
RELN	NM_173054.3	c.3209T>C	p.Met1070Thr	missense_variant	24/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RELN	ENST00000428762.6	c.3209T>C	p.Met1070Thr	missense_variant	24/65	5	NM_005045.4	P5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 03, 2017

This sequence change replaces methionine with threonine at codon 1070 of the RELN protein (p.Met1070Thr). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and threonine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a RELN-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.066	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	21
Dann	Benign	0.97
DEOGEN2	Benign	0.089	T;.;.
Eigen	Benign	0.090
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.38	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N;N;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.5	N;N;N
REVEL	Benign	0.14
Sift	Benign	0.22	T;T;T
Sift4G	Uncertain	0.0040	D;D;D
Polyphen		0.039	B;B;.
Vest4		0.54
MutPred		0.49		Gain of glycosylation at M1070 (P = 0.0085);Gain of glycosylation at M1070 (P = 0.0085);Gain of glycosylation at M1070 (P = 0.0085);
MVP		0.11
MPC		0.23
ClinPred		0.66	D
GERP RS		5.5
Varity_R		0.31
gMVP		0.32

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: rs1554389059; hg19: chr7-103243875; COSMIC: COSV59000550;