7-103661529-TA-TAA

Position:

• chr7-103661529-TA-TAA

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_005045.4(RELN):​c.1290-3_1290-2insT variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0029 in 1,585,310 control chromosomes in the GnomAD database, including 78 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (46 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (32 hom.)
• Consequence: RELN NM_005045.4 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.140

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 7-103661529-T-TA is Benign according to our data. Variant chr7-103661529-T-TA is described in ClinVar as [Likely_benign]. Clinvar id is 95210.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 = 0.0143 (2143/150122) while in subpopulation AFR AF= 0.0488 (2001/41008). AF 95% confidence interval is 0.047. There are 46 homozygotes in gnomad4. There are 983 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 46 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RELN	NM_005045.4	c.1290-3_1290-2insT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000428762.6	NP_005036.2
RELN	NM_173054.3	c.1290-3_1290-2insT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NP_774959.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RELN	ENST00000428762.6	c.1290-3_1290-2insT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_005045.4	ENSP00000392423	P5

Frequencies

GnomAD3 genomes AF: 0.0142 AC: 2132 AN: 150010 Hom.: 45 Cov.: 32

Gnomad AFR AF: 0.0486

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00644

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000210

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000297

Gnomad OTH AF: 0.0117

GnomAD3 exomes AF: 0.00415 AC: 921 AN: 222016 Hom.: 12 AF XY: 0.00287 AC XY: 345 AN XY: 120308

Gnomad AFR exome AF: 0.0527

Gnomad AMR exome AF: 0.00296

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000125

Gnomad SAS exome AF: 0.000189

Gnomad FIN exome AF: 0.000102

Gnomad NFE exome AF: 0.000276

Gnomad OTH exome AF: 0.00208

GnomAD4 exome AF: 0.00172 AC: 2462 AN: 1435188 Hom.: 32 Cov.: 32 AF XY: 0.00146 AC XY: 1041 AN XY: 714686

Gnomad4 AFR exome AF: 0.0511

Gnomad4 AMR exome AF: 0.00319

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000334

Gnomad4 SAS exome AF: 0.000153

Gnomad4 FIN exome AF: 0.0000951

Gnomad4 NFE exome AF: 0.000357

Gnomad4 OTH exome AF: 0.00377

GnomAD4 genome AF: 0.0143 AC: 2143 AN: 150122 Hom.: 46 Cov.: 32 AF XY: 0.0134 AC XY: 983 AN XY: 73302

Gnomad4 AFR AF: 0.0488

Gnomad4 AMR AF: 0.00643

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000210

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000297

Gnomad4 OTH AF: 0.0116

Bravo AF: 0.0162

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 29, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 01, 2018	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Eurofins Ntd Llc (ga)	Jan 17, 2014	- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Lissencephaly, Recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

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

LitVar

Other links and lift over

dbSNP: rs146986040; hg19: chr7-103301976;