NM_005045.4:c.4937-5_4937-4dupTT

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.4937-5_4937-4dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00643 in 1,382,472 control chromosomes in the GnomAD database, including 19 homozygotes. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0054 ( 14 hom., cov: 0)

Exomes 𝑓: 0.0066 ( 5 hom. )

Consequence

RELN
NM_005045.4 splice_region, intron

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

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-G-GAA is Benign according to our data. Variant chr7-103565554-G-GAA is described in ClinVar as Benign. ClinVar VariationId is 475969.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0054 (800/148070) while in subpopulation AMR AF = 0.0427 (636/14878). AF 95% confidence interval is 0.04. There are 14 homozygotes in GnomAd4. There are 435 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 14 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.4937-5_4937-4dupTT		splice_region intron	N/A	NP_005036.2
	RELN	NM_173054.3		c.4937-5_4937-4dupTT		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.4937-4_4937-3insTT	splice_region intron	N/A	ENSP00000392423.1	P78509-1
RELN	ENST00000424685.3	TSL:5	c.4937-4_4937-3insTT	splice_region intron	N/A	ENSP00000388446.3	J3KQ66
RELN	ENST00000343529.9	TSL:5	c.4937-4_4937-3insTT	splice_region intron	N/A	ENSP00000345694.5	P78509-2

Frequencies

GnomAD3 genomes

AF:

0.00540

AC:

799

AN:

147998

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00176

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0427

Gnomad ASJ

AF:

0.00234

Gnomad EAS

AF:

0.00118

Gnomad SAS

AF:

0.000425

Gnomad FIN

AF:

0.000105

Gnomad MID

AF:

0.00325

Gnomad NFE

AF:

0.000913

Gnomad OTH

AF:

0.00735

GnomAD2 exomes

AF:

0.0167

AC:

2452

AN:

146634

AF XY:

0.0134

show subpopulations

Gnomad AFR exome

AF:

0.00489

Gnomad AMR exome

AF:

0.0968

Gnomad ASJ exome

AF:

0.00574

Gnomad EAS exome

AF:

0.00226

Gnomad FIN exome

AF:

0.00448

Gnomad NFE exome

AF:

0.00430

Gnomad OTH exome

AF:

0.0153

GnomAD4 exome

AF:

0.00656

AC:

8093

AN:

1234402

Hom.:

Cov.:

AF XY:

0.00607

AC XY:

3727

AN XY:

613978

show subpopulations

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

African (AFR)

AF:

0.00443

AC:

125

AN:

28238

American (AMR)

AF:

0.0658

AC:

2404

AN:

36516

Ashkenazi Jewish (ASJ)

AF:

0.00500

AC:

109

AN:

21790

East Asian (EAS)

AF:

0.00126

AC:

AN:

30184

South Asian (SAS)

AF:

0.00251

AC:

181

AN:

72238

European-Finnish (FIN)

AF:

0.00268

AC:

117

AN:

43636

Middle Eastern (MID)

AF:

0.00458

AC:

AN:

5020

European-Non Finnish (NFE)

AF:

0.00506

AC:

4788

AN:

946068

Other (OTH)

AF:

0.00607

AC:

308

AN:

50712

⚠️ 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: 0.302

Heterozygous variant carriers

709

1418

2127

2836

3545

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

226

452

678

904

1130

<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:

0.00540

AC:

800

AN:

148070

Hom.:

Cov.:

AF XY:

0.00604

AC XY:

435

AN XY:

72046

show subpopulations

African (AFR)

AF:

0.00176

AC:

AN:

40412

American (AMR)

AF:

0.0427

AC:

636

AN:

14878

Ashkenazi Jewish (ASJ)

AF:

0.00234

AC:

AN:

3422

East Asian (EAS)

AF:

0.00119

AC:

AN:

5060

South Asian (SAS)

AF:

0.000426

AC:

AN:

4692

European-Finnish (FIN)

AF:

0.000105

AC:

AN:

9552

Middle Eastern (MID)

AF:

0.00352

AC:

AN:

284

European-Non Finnish (NFE)

AF:

0.000913

AC:

AN:

66812

Other (OTH)

AF:

0.00678

AC:

AN:

2064

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

103

138

172

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:

0.00706

Hom.:

198

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

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

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.19

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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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