rs755797350

Variant names:

• chr7-103500731-GGCTTT-G
• rs755797350
• NM_005045.4:c.8667+9_8667+13delAAAGC

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6 BS1

The NM_005045.4(RELN):​c.8667+9_8667+13delAAAGC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000676 in 1,613,432 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000066 (0 hom.)
• Consequence: RELN NM_005045.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 0.127
• Publications: 0 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]

SLC26A5-AS1 (HGNC:55680): (SLC26A5 antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP6: Variant 7-103500731-GGCTTT-G is Benign according to our data. Variant chr7-103500731-GGCTTT-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 436520.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0000789 (12/152170) while in subpopulation AMR AF = 0.000327 (5/15272). AF 95% confidence interval is 0.000129. There are 0 homozygotes in GnomAd4. There are 8 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RELN	NM_005045.4	MANE Select	c.8667+9_8667+13delAAAGC		intron	N/A	NP_005036.2
	RELN	NM_173054.3		c.8667+9_8667+13delAAAGC		intron	N/A	NP_774959.1
	SLC26A5-AS1	NR_110141.1		n.1366-3672_1366-3668delGCTTT		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RELN	ENST00000428762.6	TSL:5 MANE Select	c.8667+9_8667+13delAAAGC		intron	N/A	ENSP00000392423.1
	SLC26A5-AS1	ENST00000422488.1	TSL:1	n.1366-3672_1366-3668delGCTTT		intron	N/A
	RELN	ENST00000424685.3	TSL:5	c.8667+9_8667+13delAAAGC		intron	N/A	ENSP00000388446.3

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000836 AC: 21 AN: 251072 AF XY: 0.000110

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000793

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000664 AC: 97 AN: 1461262 Hom.: 0 AF XY: 0.0000839 AC XY: 61 AN XY: 726962

African (AFR) AF: 0.0000299 AC: 1 AN: 33468

American (AMR) AF: 0.0000894 AC: 4 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.000232 AC: 20 AN: 86228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00275 AC: 15 AN: 5462

European-Non Finnish (NFE) AF: 0.0000450 AC: 50 AN: 1111782

Other (OTH) AF: 0.000116 AC: 7 AN: 60364

GnomAD4 genome AF: 0.0000789 AC: 12 AN: 152170 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74340

African (AFR) AF: 0.0000241 AC: 1 AN: 41434

American (AMR) AF: 0.000327 AC: 5 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000260 Hom.: 0

Bravo AF: 0.0000567

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Norman-Roberts syndrome;C4225327:Familial temporal lobe epilepsy 7 (1)
-	-	1	not provided (1)
-	1	-	not specified (1)
-	-	1	RELN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.13
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs755797350; hg19: chr7-103141178;