rs755797350

chr7-103500731-GGCTTT-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 BS1

The NM_005045.4(RELN):c.8667+9_8667+13del 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

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

Verdict is Likely_benign. Variant got -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 id is 436520.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}.
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RELN	NM_005045.4	c.8667+9_8667+13del		intron_variant		ENST00000428762.6
SLC26A5-AS1	NR_110141.1	n.1366-3672_1366-3668del		intron_variant, non_coding_transcript_variant
RELN	NM_173054.3	c.8667+9_8667+13del		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RELN	ENST00000428762.6	c.8667+9_8667+13del		intron_variant		5	NM_005045.4	P5
SLC26A5-AS1	ENST00000422488.1	n.1366-3672_1366-3668del		intron_variant, non_coding_transcript_variant		1

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

GnomAD3 exomes AF: 0.0000836 AC: 21 AN: 251072 Hom.: 0 AF XY: 0.000110 AC XY: 15 AN XY: 135758

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 SAS exome AF: 0.000261

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

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000450

Gnomad4 OTH exome AF: 0.000116

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

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000260 Hom.: 0

Bravo AF: 0.0000567

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Dec 13, 2016

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Aug 04, 2023

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 28, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

RELN-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 27, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs755797350; hg19: chr7-103141178;