7-103565554-GAA-GAAA

Variant names:

• chr7-103565554-G-GA
• rs35268159
• NM_005045.4:c.4937-4dupT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_005045.4(RELN):​c.4937-4dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (5830 hom., cov: 0)
  • Exomes 𝑓: 0.30 (9657 hom.)
  • Failed GnomAD Quality Control
• Consequence: RELN NM_005045.4 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.186
• Publications: 7 publications found

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

ACMG classification

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

• BP6: Variant 7-103565554-G-GA is Benign according to our data. Variant chr7-103565554-G-GA is described in ClinVar as Benign. ClinVar VariationId is 358398.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.299 is higher than 0.05.

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.4937-4dupT		splice_region intron	N/A	NP_005036.2
	RELN	NM_173054.3		c.4937-4dupT		splice_region intron	N/A	NP_774959.1	P78509-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RELN	ENST00000428762.6	TSL:5 MANE Select	c.4937-4_4937-3insT		splice_region intron	N/A	ENSP00000392423.1	P78509-1
	RELN	ENST00000424685.3	TSL:5	c.4937-4_4937-3insT		splice_region intron	N/A	ENSP00000388446.3	J3KQ66
	RELN	ENST00000343529.9	TSL:5	c.4937-4_4937-3insT		splice_region intron	N/A	ENSP00000345694.5	P78509-2

Frequencies

GnomAD3 genomes AF: 0.280 AC: 41368 AN: 147874 Hom.: 5827 Cov.: 0

Gnomad AFR AF: 0.286

Gnomad AMI AF: 0.174

Gnomad AMR AF: 0.236

Gnomad ASJ AF: 0.277

Gnomad EAS AF: 0.0792

Gnomad SAS AF: 0.267

Gnomad FIN AF: 0.279

Gnomad MID AF: 0.380

Gnomad NFE AF: 0.302

Gnomad OTH AF: 0.315

GnomAD2 exomes AF: 0.348 AC: 51032 AN: 146634 AF XY: 0.355

Gnomad AFR exome AF: 0.360

Gnomad AMR exome AF: 0.252

Gnomad ASJ exome AF: 0.365

Gnomad EAS exome AF: 0.172

Gnomad FIN exome AF: 0.375

Gnomad NFE exome AF: 0.381

Gnomad OTH exome AF: 0.364

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.304 AC: 352640 AN: 1160146 Hom.: 9657 Cov.: 32 AF XY: 0.304 AC XY: 175394 AN XY: 576508

African (AFR) AF: 0.305 AC: 8082 AN: 26520

American (AMR) AF: 0.203 AC: 6867 AN: 33752

Ashkenazi Jewish (ASJ) AF: 0.299 AC: 6058 AN: 20268

East Asian (EAS) AF: 0.105 AC: 2698 AN: 25580

South Asian (SAS) AF: 0.282 AC: 18951 AN: 67184

European-Finnish (FIN) AF: 0.293 AC: 12043 AN: 41148

Middle Eastern (MID) AF: 0.345 AC: 1679 AN: 4868

European-Non Finnish (NFE) AF: 0.316 AC: 281870 AN: 893320

Other (OTH) AF: 0.303 AC: 14392 AN: 47506

GnomAD4 genome AF: 0.280 AC: 41390 AN: 147946 Hom.: 5830 Cov.: 0 AF XY: 0.278 AC XY: 20016 AN XY: 72000

African (AFR) AF: 0.286 AC: 11533 AN: 40386

American (AMR) AF: 0.236 AC: 3506 AN: 14864

Ashkenazi Jewish (ASJ) AF: 0.277 AC: 947 AN: 3422

East Asian (EAS) AF: 0.0793 AC: 401 AN: 5058

South Asian (SAS) AF: 0.268 AC: 1256 AN: 4688

European-Finnish (FIN) AF: 0.279 AC: 2661 AN: 9524

Middle Eastern (MID) AF: 0.384 AC: 109 AN: 284

European-Non Finnish (NFE) AF: 0.302 AC: 20176 AN: 66768

Other (OTH) AF: 0.313 AC: 645 AN: 2058

Alfa AF: 0.200 Hom.: 198

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Lissencephaly, Recessive (1)
-	-	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		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs35268159; hg19: chr7-103206001; COSMIC: COSV59000683;