rs200289289

Variant names:

• chr7-103700935-C-T
• rs200289289
• NM_005045.4:c.877G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_005045.4(RELN):​c.877G>A​(p.Asp293Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000258 in 1,609,810 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (0 hom.)
• Consequence: RELN NM_005045.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:4
• Conservation: PhyloP100: 5.46
• 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: Orphanet, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Illumina
• 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.060350657).
• BP6: Variant 7-103700935-C-T is Benign according to our data. Variant chr7-103700935-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 393143.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000329 (50/152092) while in subpopulation NFE AF = 0.000309 (21/67972). AF 95% confidence interval is 0.000207. There are 0 homozygotes in GnomAd4. There are 30 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005045.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RELN	NM_005045.4	MANE Select	c.877G>A	p.Asp293Asn	missense	Exon 9 of 65	NP_005036.2
	RELN	NM_173054.3		c.877G>A	p.Asp293Asn	missense	Exon 9 of 64	NP_774959.1	P78509-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RELN	ENST00000428762.6	TSL:5 MANE Select	c.877G>A	p.Asp293Asn	missense	Exon 9 of 65	ENSP00000392423.1	P78509-1
	RELN	ENST00000424685.3	TSL:5	c.877G>A	p.Asp293Asn	missense	Exon 9 of 65	ENSP00000388446.3	J3KQ66
	RELN	ENST00000343529.9	TSL:5	c.877G>A	p.Asp293Asn	missense	Exon 9 of 64	ENSP00000345694.5	P78509-2

Frequencies

GnomAD3 genomes AF: 0.000329 AC: 50 AN: 152092 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000450 AC: 113 AN: 251260 AF XY: 0.000442

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.00466

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000463

Gnomad NFE exome AF: 0.000387

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000251 AC: 366 AN: 1457718 Hom.: 0 Cov.: 29 AF XY: 0.000276 AC XY: 200 AN XY: 725406

African (AFR) AF: 0.000180 AC: 6 AN: 33370

American (AMR) AF: 0.000268 AC: 12 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00437 AC: 114 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39638

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86138

European-Finnish (FIN) AF: 0.000431 AC: 23 AN: 53356

Middle Eastern (MID) AF: 0.000522 AC: 3 AN: 5752

European-Non Finnish (NFE) AF: 0.000152 AC: 169 AN: 1108398

Other (OTH) AF: 0.000614 AC: 37 AN: 60268

GnomAD4 genome AF: 0.000329 AC: 50 AN: 152092 Hom.: 0 Cov.: 32 AF XY: 0.000404 AC XY: 30 AN XY: 74304

African (AFR) AF: 0.0000241 AC: 1 AN: 41440

American (AMR) AF: 0.0000655 AC: 1 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00576 AC: 20 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 67972

Other (OTH) AF: 0.00144 AC: 3 AN: 2086

Alfa AF: 0.000554 Hom.: 0

Bravo AF: 0.000336

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000313 AC: 38

EpiCase AF: 0.000655

EpiControl AF: 0.000415

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	2	not provided (4)
-	1	-	Inborn genetic diseases (1)
-	1	-	Norman-Roberts syndrome (1)
-	-	1	Norman-Roberts syndrome;C4225327:Familial temporal lobe epilepsy 7 (1)
-	1	-	not specified (1)
-	-	1	RELN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.071	T
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.0092	T
MetaRNN	Benign	0.060	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		5.5
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.046
Sift	Benign	0.38	T
Sift4G	Uncertain	0.029	D
Polyphen		0.16	B
Vest4		0.80
MVP		0.58
MPC		0.18
ClinPred		0.019	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.14
gMVP		0.54
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs200289289; hg19: chr7-103341382;