NM_005045.4:c.32T>G

Variant names:

• chr7-103989325-A-C
• rs764120718
• NM_005045.4:c.32T>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BS1_Supporting

The NM_005045.4(RELN):​c.32T>G​(p.Phe11Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000279 in 1,434,108 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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. F11L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: RELN NM_005045.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.12
• Publications: 1 publications found

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]

RELN Gene-Disease associations (from GenCC):

• lissencephaly with cerebellar hypoplasia

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Norman-Roberts syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Illumina, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, G2P, PanelApp Australia
• familial temporal lobe epilepsy 7

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• autosomal dominant epilepsy with auditory features

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• ankylosing spondylitis

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• complex neurodevelopmental disorder

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15835962).
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00000279 (4/1434108) while in subpopulation MID AF = 0.000732 (4/5464). AF 95% confidence interval is 0.00025. There are 0 homozygotes in GnomAdExome4. There are 2 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RELN	NM_005045.4	c.32T>G	p.Phe11Cys	missense_variant	Exon 1 of 65	ENST00000428762.6	NP_005036.2
RELN	NM_173054.3	c.32T>G	p.Phe11Cys	missense_variant	Exon 1 of 64		NP_774959.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RELN	ENST00000428762.6	c.32T>G	p.Phe11Cys	missense_variant	Exon 1 of 65	5	NM_005045.4	ENSP00000392423.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000439 AC: 1 AN: 227732 AF XY: 0.00000794

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000983

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000279 AC: 4 AN: 1434108 Hom.: 0 Cov.: 32 AF XY: 0.00000281 AC XY: 2 AN XY: 712840

African (AFR) AF: 0.00 AC: 0 AN: 32710

American (AMR) AF: 0.00 AC: 0 AN: 43982

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25728

East Asian (EAS) AF: 0.00 AC: 0 AN: 38378

South Asian (SAS) AF: 0.00 AC: 0 AN: 84456

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50558

Middle Eastern (MID) AF: 0.000732 AC: 4 AN: 5464

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1093730

Other (OTH) AF: 0.00 AC: 0 AN: 59102

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000832 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Jan 13, 2015

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

May 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 11 of the RELN protein (p.Phe11Cys). This variant is present in population databases (rs764120718, gnomAD 0.001%). This variant has not been reported in the literature in individuals affected with RELN-related conditions. ClinVar contains an entry for this variant (Variation ID: 212036). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The cysteine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.063	T;.;.
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.69	T;T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.16	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N;.
PhyloP100		2.1
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-0.97	N;N;N
REVEL	Benign	0.048
Sift	Benign	0.038	D;D;D
Sift4G	Uncertain	0.031	D;D;D
Polyphen		0.0	B;B;.
Vest4		0.29
MutPred		0.32		Gain of catalytic residue at L12 (P = 0.0305);Gain of catalytic residue at L12 (P = 0.0305);Gain of catalytic residue at L12 (P = 0.0305);
MVP		0.043
MPC		0.25
ClinPred		0.23	T
GERP RS		3.1
PromoterAI		-0.039	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.080
gMVP		0.59
Mutation Taster		=87/13	polymorphism

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: rs764120718; hg19: chr7-103629772;