7-103989356-TGCCGCCGCCGCCGCC-TGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCC

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_005045.4(RELN):c.-18_-1dupGGCGGCGGCGGCGGCGGC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.013 ( 41 hom., cov: 0)

Exomes 𝑓: 0.0011 ( 26 hom. )

Failed GnomAD Quality Control

Consequence

RELN
NM_005045.4 5_prime_UTR

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 2.06

Publications

2 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: Illumina, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, G2P, PanelApp Australia
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 -9 ACMG points.

BP6

Variant 7-103989356-T-TGCCGCCGCCGCCGCCGCC is Benign according to our data. Variant chr7-103989356-T-TGCCGCCGCCGCCGCCGCC is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 358426.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0133 (1980/148346) while in subpopulation AFR AF = 0.0404 (1630/40300). AF 95% confidence interval is 0.0388. There are 41 homozygotes in GnomAd4. There are 940 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 41 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RELN	NM_005045.4 link	c.-18_-1dupGGCGGCGGCGGCGGCGGC		5_prime_UTR_variant	Exon 1 of 65	ENST00000428762.6	NP_005036.2
RELN	NM_173054.3 link	c.-18_-1dupGGCGGCGGCGGCGGCGGC		5_prime_UTR_variant	Exon 1 of 64		NP_774959.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RELN	ENST00000428762.6 link	c.-18_-1dupGGCGGCGGCGGCGGCGGC		5_prime_UTR_variant	Exon 1 of 65	5	NM_005045.4	ENSP00000392423.1

Frequencies

GnomAD3 genomes

AF:

0.0133

AC:

1979

AN:

148248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0405

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00552

Gnomad ASJ

AF:

0.00638

Gnomad EAS

AF:

0.00891

Gnomad SAS

AF:

0.00617

Gnomad FIN

AF:

0.000398

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00215

Gnomad OTH

AF:

0.0128

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00109

AC:

1372

AN:

1259028

Hom.:

Cov.:

AF XY:

0.00104

AC XY:

647

AN XY:

620162

show subpopulations

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

African (AFR)

AF:

0.0172

AC:

420

AN:

24468

American (AMR)

AF:

0.000707

AC:

AN:

21204

Ashkenazi Jewish (ASJ)

AF:

0.00153

AC:

AN:

20980

East Asian (EAS)

AF:

0.00226

AC:

AN:

26966

South Asian (SAS)

AF:

0.000924

AC:

AN:

56288

European-Finnish (FIN)

AF:

0.000238

AC:

AN:

37792

Middle Eastern (MID)

AF:

0.000722

AC:

AN:

4156

European-Non Finnish (NFE)

AF:

0.000675

AC:

685

AN:

1015162

Other (OTH)

AF:

0.00183

AC:

AN:

52012

⚠️ 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: 0.385

Heterozygous variant carriers

143

191

239

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

126

168

210

<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:

0.0133

AC:

1980

AN:

148346

Hom.:

Cov.:

AF XY:

0.0130

AC XY:

940

AN XY:

72336

show subpopulations

African (AFR)

AF:

0.0404

AC:

1630

AN:

40300

American (AMR)

AF:

0.00552

AC:

AN:

15048

Ashkenazi Jewish (ASJ)

AF:

0.00638

AC:

AN:

3446

East Asian (EAS)

AF:

0.00894

AC:

AN:

4698

South Asian (SAS)

AF:

0.00618

AC:

AN:

4692

European-Finnish (FIN)

AF:

0.000398

AC:

AN:

10060

Middle Eastern (MID)

AF:

0.00

AC:

AN:

278

European-Non Finnish (NFE)

AF:

0.00215

AC:

144

AN:

66872

Other (OTH)

AF:

0.0126

AC:

AN:

2060

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

168

253

337

421

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<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:

0.00124

Hom.:

609

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Lissencephaly, Recessive

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Jan 18, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.1

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over