7-103565554-GAA-GA

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_005045.4(RELN):c.4937-4delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00741 in 1,295,968 control chromosomes in the GnomAD database, including 4 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0031 ( 1 hom., cov: 0)

Exomes 𝑓: 0.0080 ( 3 hom. )

Consequence

RELN
NM_005045.4 splice_region, intron

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.186

Publications

7 publications found

Variant links:

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

RELN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP6

Variant 7-103565554-GA-G is Benign according to our data. Variant chr7-103565554-GA-G is described in ClinVar as Benign. ClinVar VariationId is 196903.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 = 0.0031 (458/147966) while in subpopulation AFR AF = 0.00965 (390/40396). AF 95% confidence interval is 0.00886. There are 1 homozygotes in GnomAd4. There are 223 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 3 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.4937-4delT		splice_region intron	N/A	NP_005036.2
	RELN	NM_173054.3		c.4937-4delT		splice_region intron	N/A	NP_774959.1	P78509-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RELN	ENST00000428762.6	TSL:5 MANE Select	c.4937-4delT	splice_region intron	N/A	ENSP00000392423.1	P78509-1
RELN	ENST00000424685.3	TSL:5	c.4937-4delT	splice_region intron	N/A	ENSP00000388446.3	J3KQ66
RELN	ENST00000343529.9	TSL:5	c.4937-4delT	splice_region intron	N/A	ENSP00000345694.5	P78509-2

Frequencies

GnomAD3 genomes

AF:

0.00309

AC:

457

AN:

147892

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00101

Gnomad ASJ

AF:

0.000584

Gnomad EAS

AF:

0.000788

Gnomad SAS

AF:

0.000212

Gnomad FIN

AF:

0.000631

Gnomad MID

AF:

0.00325

Gnomad NFE

AF:

0.000524

Gnomad OTH

AF:

0.00196

GnomAD2 exomes

AF:

0.0342

AC:

5015

AN:

146634

AF XY:

0.0339

show subpopulations

Gnomad AFR exome

AF:

0.0486

Gnomad AMR exome

AF:

0.0318

Gnomad ASJ exome

AF:

0.0171

Gnomad EAS exome

AF:

0.0736

Gnomad FIN exome

AF:

0.0313

Gnomad NFE exome

AF:

0.0318

Gnomad OTH exome

AF:

0.0251

GnomAD4 exome

AF:

0.00797

AC:

9144

AN:

1148002

Hom.:

Cov.:

AF XY:

0.00816

AC XY:

4640

AN XY:

568786

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0204

AC:

534

AN:

26114

American (AMR)

AF:

0.0216

AC:

686

AN:

31744

Ashkenazi Jewish (ASJ)

AF:

0.00881

AC:

171

AN:

19400

East Asian (EAS)

AF:

0.0178

AC:

419

AN:

23584

South Asian (SAS)

AF:

0.0127

AC:

810

AN:

63636

European-Finnish (FIN)

AF:

0.0132

AC:

520

AN:

39460

Middle Eastern (MID)

AF:

0.00395

AC:

AN:

4812

European-Non Finnish (NFE)

AF:

0.00631

AC:

5629

AN:

892490

Other (OTH)

AF:

0.00761

AC:

356

AN:

46762

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.265

Heterozygous variant carriers

1367

2734

4100

5467

6834

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

232

464

696

928

1160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00310

AC:

458

AN:

147966

Hom.:

Cov.:

AF XY:

0.00310

AC XY:

223

AN XY:

71996

show subpopulations

African (AFR)

AF:

0.00965

AC:

390

AN:

40396

American (AMR)

AF:

0.00101

AC:

AN:

14870

Ashkenazi Jewish (ASJ)

AF:

0.000584

AC:

AN:

3422

East Asian (EAS)

AF:

0.000791

AC:

AN:

5060

South Asian (SAS)

AF:

0.000213

AC:

AN:

4694

European-Finnish (FIN)

AF:

0.000631

AC:

AN:

9516

Middle Eastern (MID)

AF:

0.00352

AC:

AN:

284

European-Non Finnish (NFE)

AF:

0.000524

AC:

AN:

66768

Other (OTH)

AF:

0.00194

AC:

AN:

2062

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

119

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0382

Hom.:

198

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

Norman-Roberts syndrome (1)

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.19

Mutation Taster

=97/3

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over