chr7-103989356-T-TGCC

Variant names:

Variant summary

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

The NM_005045.4(RELN):c.-3_-1dupGGC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00678 in 1,316,650 control chromosomes in the GnomAD database, including 23 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0017 ( 2 hom., cov: 0)

Exomes 𝑓: 0.0074 ( 21 hom. )

Consequence

RELN
NM_005045.4 5_prime_UTR

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

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: 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 -9 ACMG points.

BP6

Variant 7-103989356-T-TGCC is Benign according to our data. Variant chr7-103989356-T-TGCC is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 358423.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00165 (245/148280) while in subpopulation AFR AF = 0.00298 (120/40304). AF 95% confidence interval is 0.00254. There are 2 homozygotes in GnomAd4. There are 125 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 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.-3_-1dupGGC		5_prime_UTR	Exon 1 of 65	NP_005036.2
	RELN	NM_173054.3		c.-3_-1dupGGC		5_prime_UTR	Exon 1 of 64	NP_774959.1	P78509-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RELN	ENST00000428762.6	TSL:5 MANE Select	c.-3_-1dupGGC	5_prime_UTR	Exon 1 of 65	ENSP00000392423.1	P78509-1
RELN	ENST00000424685.3	TSL:5	c.-3_-1dupGGC	5_prime_UTR	Exon 1 of 65	ENSP00000388446.3	J3KQ66
RELN	ENST00000343529.9	TSL:5	c.-3_-1dupGGC	5_prime_UTR	Exon 1 of 64	ENSP00000345694.5	P78509-2

Frequencies

GnomAD3 genomes

AF:

0.00163

AC:

241

AN:

148180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00289

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000533

Gnomad ASJ

AF:

0.00174

Gnomad EAS

AF:

0.000849

Gnomad SAS

AF:

0.000213

Gnomad FIN

AF:

0.000399

Gnomad MID

AF:

0.00338

Gnomad NFE

AF:

0.00142

Gnomad OTH

AF:

0.00295

GnomAD2 exomes

AF:

0.0113

AC:

720

AN:

63892

AF XY:

0.0118

show subpopulations

Gnomad AFR exome

AF:

0.00490

Gnomad AMR exome

AF:

0.0113

Gnomad ASJ exome

AF:

0.00799

Gnomad EAS exome

AF:

0.0428

Gnomad FIN exome

AF:

0.0109

Gnomad NFE exome

AF:

0.00833

Gnomad OTH exome

AF:

0.0143

GnomAD4 exome

AF:

0.00743

AC:

8678

AN:

1168370

Hom.:

Cov.:

AF XY:

0.00775

AC XY:

4436

AN XY:

572536

show subpopulations

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

African (AFR)

AF:

0.00844

AC:

194

AN:

22998

American (AMR)

AF:

0.00687

AC:

137

AN:

19948

Ashkenazi Jewish (ASJ)

AF:

0.00733

AC:

144

AN:

19656

East Asian (EAS)

AF:

0.00737

AC:

156

AN:

21162

South Asian (SAS)

AF:

0.0276

AC:

1282

AN:

46420

European-Finnish (FIN)

AF:

0.00571

AC:

199

AN:

34858

Middle Eastern (MID)

AF:

0.00676

AC:

AN:

3846

European-Non Finnish (NFE)

AF:

0.00654

AC:

6221

AN:

951798

Other (OTH)

AF:

0.00669

AC:

319

AN:

47684

⚠️ 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: 0.312

Heterozygous variant carriers

902

1805

2707

3610

4512

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

266

532

798

1064

1330

<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:

0.00165

AC:

245

AN:

148280

Hom.:

Cov.:

AF XY:

0.00173

AC XY:

125

AN XY:

72300

show subpopulations

African (AFR)

AF:

0.00298

AC:

120

AN:

40304

American (AMR)

AF:

0.000532

AC:

AN:

15038

Ashkenazi Jewish (ASJ)

AF:

0.00174

AC:

AN:

3446

East Asian (EAS)

AF:

0.000852

AC:

AN:

4696

South Asian (SAS)

AF:

0.000213

AC:

AN:

4690

European-Finnish (FIN)

AF:

0.000399

AC:

AN:

10026

Middle Eastern (MID)

AF:

0.00360

AC:

AN:

278

European-Non Finnish (NFE)

AF:

0.00142

AC:

AN:

66852

Other (OTH)

AF:

0.00292

AC:

AN:

2058

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

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:

0.00

Hom.:

609

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Lissencephaly, Recessive (1)

RELN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over