rs79499902

Variant names:

• chr7-103561880-C-T
• rs79499902
• NM_005045.4:c.5284G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005045.4(RELN):​c.5284G>A​(p.Val1762Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00413 in 1,565,482 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (16 hom., cov: 30)
  • Exomes 𝑓: 0.0035 (32 hom.)
• Consequence: RELN NM_005045.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:11
• Conservation: PhyloP100: 4.57
• Publications: 15 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0073706806).
• BP6: Variant 7-103561880-C-T is Benign according to our data. Variant chr7-103561880-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 130127.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0101 (1480/146512) while in subpopulation AFR AF = 0.0274 (1093/39888). AF 95% confidence interval is 0.0261. There are 16 homozygotes in GnomAd4. There are 715 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 16 AR,AD gene

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.5284G>A	p.Val1762Ile	missense	Exon 35 of 65	NP_005036.2
	RELN	NM_173054.3		c.5284G>A	p.Val1762Ile	missense	Exon 35 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.5284G>A	p.Val1762Ile	missense	Exon 35 of 65	ENSP00000392423.1	P78509-1
	RELN	ENST00000424685.3	TSL:5	c.5284G>A	p.Val1762Ile	missense	Exon 35 of 65	ENSP00000388446.3	J3KQ66
	RELN	ENST00000343529.9	TSL:5	c.5284G>A	p.Val1762Ile	missense	Exon 35 of 64	ENSP00000345694.5	P78509-2

Frequencies

GnomAD3 genomes AF: 0.0101 AC: 1477 AN: 146398 Hom.: 16 Cov.: 30

Gnomad AFR AF: 0.0274

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00646

Gnomad ASJ AF: 0.00958

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00206

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0164

Gnomad NFE AF: 0.00336

Gnomad OTH AF: 0.0113

GnomAD2 exomes AF: 0.00475 AC: 1192 AN: 251180 AF XY: 0.00440

Gnomad AFR exome AF: 0.0289

Gnomad AMR exome AF: 0.00374

Gnomad ASJ exome AF: 0.0112

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00328

Gnomad OTH exome AF: 0.00408

GnomAD4 exome AF: 0.00352 AC: 4989 AN: 1418970 Hom.: 32 Cov.: 34 AF XY: 0.00354 AC XY: 2499 AN XY: 706156

African (AFR) AF: 0.0302 AC: 969 AN: 32138

American (AMR) AF: 0.00423 AC: 184 AN: 43464

Ashkenazi Jewish (ASJ) AF: 0.0132 AC: 318 AN: 24152

East Asian (EAS) AF: 0.00 AC: 0 AN: 36048

South Asian (SAS) AF: 0.00259 AC: 222 AN: 85848

European-Finnish (FIN) AF: 0.000202 AC: 10 AN: 49614

Middle Eastern (MID) AF: 0.0153 AC: 85 AN: 5546

European-Non Finnish (NFE) AF: 0.00263 AC: 2858 AN: 1084870

Other (OTH) AF: 0.00599 AC: 343 AN: 57290

GnomAD4 genome AF: 0.0101 AC: 1480 AN: 146512 Hom.: 16 Cov.: 30 AF XY: 0.0101 AC XY: 715 AN XY: 70948

African (AFR) AF: 0.0274 AC: 1093 AN: 39888

American (AMR) AF: 0.00645 AC: 92 AN: 14270

Ashkenazi Jewish (ASJ) AF: 0.00958 AC: 33 AN: 3444

East Asian (EAS) AF: 0.00 AC: 0 AN: 4740

South Asian (SAS) AF: 0.00206 AC: 9 AN: 4374

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9354

Middle Eastern (MID) AF: 0.0141 AC: 4 AN: 284

European-Non Finnish (NFE) AF: 0.00336 AC: 226 AN: 67212

Other (OTH) AF: 0.0112 AC: 23 AN: 2050

Alfa AF: 0.00593 Hom.: 15

Bravo AF: 0.0115

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.0238 AC: 105

ESP6500EA AF: 0.00442 AC: 38

ExAC AF: 0.00516 AC: 626

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.00458

EpiControl AF: 0.00480

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	2	not provided (2)
-	-	1	Norman-Roberts syndrome (1)
-	-	1	Norman-Roberts syndrome;C4225327:Familial temporal lobe epilepsy 7 (1)
-	-	1	Norman-Roberts syndrome;C4225327:Familial temporal lobe epilepsy 7;CN030884:Epilepsy, familial temporal lobe, 1 (1)
1	-	-	Self-limited epilepsy with centrotemporal spikes (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.039
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0074	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.77	N
PhyloP100		4.6
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.26	N
REVEL	Benign	0.15
Sift	Benign	0.062	T
Sift4G	Benign	0.19	T
Polyphen		0.0020	B
Vest4		0.30
MVP		0.068
MPC		0.14
ClinPred		0.012	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.10
gMVP		0.41
Mutation Taster		=95/5	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: rs79499902; hg19: chr7-103202327;