rs77664442

chr7-103553798-A-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_005045.4(RELN):c.5831T>G(p.Phe1944Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00433 in 1,613,968 control chromosomes in the GnomAD database, including 255 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. F1944F) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.023 (136 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (119 hom.)
• Consequence: RELN NM_005045.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 8.95

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 Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, RELN
• BP4: Computational evidence support a benign effect (MetaRNN=0.004383892).
• BP6: Variant 7-103553798-A-C is Benign according to our data. Variant chr7-103553798-A-C is described in ClinVar as [Benign]. Clinvar id is 130131.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-103553798-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0763 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RELN	NM_005045.4	c.5831T>G	p.Phe1944Cys	missense_variant	39/65	ENST00000428762.6
RELN	NM_173054.3	c.5831T>G	p.Phe1944Cys	missense_variant	39/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RELN	ENST00000428762.6	c.5831T>G	p.Phe1944Cys	missense_variant	39/65	5	NM_005045.4	P5

Frequencies

GnomAD3 genomes AF: 0.0227 AC: 3454 AN: 152160 Hom.: 136 Cov.: 32

Gnomad AFR AF: 0.0786

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.0149

GnomAD3 exomes AF: 0.00612 AC: 1536 AN: 251180 Hom.: 62 AF XY: 0.00460 AC XY: 625 AN XY: 135758

Gnomad AFR exome AF: 0.0817

Gnomad AMR exome AF: 0.00448

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000194

Gnomad OTH exome AF: 0.00327

GnomAD4 exome AF: 0.00242 AC: 3530 AN: 1461690 Hom.: 119 Cov.: 32 AF XY: 0.00209 AC XY: 1518 AN XY: 727170

Gnomad4 AFR exome AF: 0.0824

Gnomad4 AMR exome AF: 0.00541

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000255

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000147

Gnomad4 OTH exome AF: 0.00535

GnomAD4 genome AF: 0.0227 AC: 3463 AN: 152278 Hom.: 136 Cov.: 32 AF XY: 0.0223 AC XY: 1657 AN XY: 74464

Gnomad4 AFR AF: 0.0786

Gnomad4 AMR AF: 0.00915

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.00557 Hom.: 51

Bravo AF: 0.0261

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0815 AC: 359

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00747 AC: 907

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 31, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Norman-Roberts syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.36
Cadd	Pathogenic	27
Dann	Uncertain	0.99
DEOGEN2	Benign	0.14	T;.;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D;D
MetaRNN	Benign	0.0044	T;T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.1	L;L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-2.1	N;N;N
REVEL	Benign	0.22
Sift	Uncertain	0.0080	D;D;D
Sift4G	Uncertain	0.0040	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.64
MVP		0.21
MPC		0.60
ClinPred		0.022	T
GERP RS		6.1
Varity_R		0.31
gMVP		0.67

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: rs77664442; hg19: chr7-103194245;