7-103472745-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_005045.4(RELN):c.*67G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0125 in 1,245,096 control chromosomes in the GnomAD database, including 191 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (71 hom., cov: 32)
  • Exomes 𝑓: 0.011 (120 hom.)
• Consequence: RELN NM_005045.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.610

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 Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 7-103472745-C-T is Benign according to our data. Variant chr7-103472745-C-T is described in ClinVar as [Benign]. Clinvar id is 358373.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0504 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RELN	NM_005045.4	c.*67G>A		3_prime_UTR_variant	65/65	ENST00000428762.6
SLC26A5-AS1	NR_110141.1	n.1365+26077C>T		intron_variant, non_coding_transcript_variant
RELN	NM_173054.3	c.*67G>A		3_prime_UTR_variant	64/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RELN	ENST00000428762.6	c.*67G>A		3_prime_UTR_variant	65/65	5	NM_005045.4	P5
SLC26A5-AS1	ENST00000422488.1	n.1365+26077C>T		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.0223 AC: 3387 AN: 151832 Hom.: 70 Cov.: 32

Gnomad AFR AF: 0.0522

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0160

Gnomad ASJ AF: 0.00750

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00540

Gnomad FIN AF: 0.000949

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0123

Gnomad OTH AF: 0.0216

GnomAD4 exome AF: 0.0111 AC: 12160 AN: 1093146 Hom.: 120 Cov.: 14 AF XY: 0.0109 AC XY: 6122 AN XY: 560188

Gnomad4 AFR exome AF: 0.0518

Gnomad4 AMR exome AF: 0.0121

Gnomad4 ASJ exome AF: 0.00964

Gnomad4 EAS exome AF: 0.0000266

Gnomad4 SAS exome AF: 0.00608

Gnomad4 FIN exome AF: 0.00118

Gnomad4 NFE exome AF: 0.0112

Gnomad4 OTH exome AF: 0.0128

GnomAD4 genome AF: 0.0223 AC: 3389 AN: 151950 Hom.: 71 Cov.: 32 AF XY: 0.0211 AC XY: 1565 AN XY: 74238

Gnomad4 AFR AF: 0.0522

Gnomad4 AMR AF: 0.0160

Gnomad4 ASJ AF: 0.00750

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00499

Gnomad4 FIN AF: 0.000949

Gnomad4 NFE AF: 0.0122

Gnomad4 OTH AF: 0.0219

Alfa AF: 0.0175 Hom.: 9

Bravo AF: 0.0245

Asia WGS AF: 0.00577 AC: 20 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Norman-Roberts syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 27, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
Cadd	Benign	9.7
Dann	Benign	0.84
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs112874175; hg19: chr7-103113192;