rs1554362509

Positions:

• chr7-103490814-C-G
• chr7-103490814-C-T

Variant summary

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

The NM_005045.4(RELN):​c.9459G>C​(p.Gln3153His) variant causes a missense change involving the alteration of a non-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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RELN NM_005045.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.339

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]

SLC26A5-AS1 (HGNC:55680): (SLC26A5 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), RELN. . Gene score misZ 2.2497 (greater than the threshold 3.09). Trascript score misZ 4.2638 (greater than threshold 3.09). GenCC has associacion of gene with ankylosing spondylitis, lissencephaly with cerebellar hypoplasia, Norman-Roberts syndrome, complex neurodevelopmental disorder, autosomal dominant epilepsy with auditory features, familial temporal lobe epilepsy 7.
• BP4: Computational evidence support a benign effect (MetaRNN=0.301624).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RELN	NM_005045.4	c.9459G>C	p.Gln3153His	missense_variant	59/65	ENST00000428762.6	NP_005036.2
SLC26A5-AS1	NR_110141.1	n.1366-13590C>G		intron_variant, non_coding_transcript_variant
RELN	NM_173054.3	c.9459G>C	p.Gln3153His	missense_variant	59/64		NP_774959.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RELN	ENST00000428762.6	c.9459G>C	p.Gln3153His	missense_variant	59/65	5	NM_005045.4	ENSP00000392423	P5
SLC26A5-AS1	ENST00000422488.1	n.1366-13590C>G		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Labcorp Genetics (formerly Invitae), Labcorp

Mar 04, 2020

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 output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The histidine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with RELN-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamine with histidine at codon 3153 of the RELN protein (p.Gln3153His). The glutamine residue is moderately conserved and there is a small physicochemical difference between glutamine and histidine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	13
DANN	Uncertain	0.98
DEOGEN2	Benign	0.11	T;.;.
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.47
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.83	T;T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.30	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.71	N;N;.
MutationTaster	Benign	0.98	D;D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.8	N;N;N
REVEL	Benign	0.10
Sift	Benign	0.30	T;T;T
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		0.61	P;D;.
Vest4		0.33
MutPred		0.34		Gain of disorder (P = 0.1579);Gain of disorder (P = 0.1579);Gain of disorder (P = 0.1579);
MVP		0.65
MPC		0.29
ClinPred		0.44	T
GERP RS		0.57
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.48

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: rs1554362509; hg19: chr7-103131261;