7-103989331-T-G

Variant names:

• chr7-103989331-T-G
• rs115165703
• NM_005045.4:c.26A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005045.4(RELN):​c.26A>C​(p.Gln9Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00402 in 1,576,612 control chromosomes in the GnomAD database, including 227 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q9L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.022 (118 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (109 hom.)
• Consequence: RELN NM_005045.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.32
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018935204).
• BP6: Variant 7-103989331-T-G is Benign according to our data. Variant chr7-103989331-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0746 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.26A>C	p.Gln9Pro	missense	Exon 1 of 65	NP_005036.2
	RELN	NM_173054.3		c.26A>C	p.Gln9Pro	missense	Exon 1 of 64	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.26A>C	p.Gln9Pro	missense	Exon 1 of 65	ENSP00000392423.1	P78509-1
	RELN	ENST00000424685.3	TSL:5	c.26A>C	p.Gln9Pro	missense	Exon 1 of 65	ENSP00000388446.3	J3KQ66
	RELN	ENST00000343529.9	TSL:5	c.26A>C	p.Gln9Pro	missense	Exon 1 of 64	ENSP00000345694.5	P78509-2

Frequencies

GnomAD3 genomes AF: 0.0219 AC: 3265 AN: 149306 Hom.: 118 Cov.: 32

Gnomad AFR AF: 0.0768

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00865

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000217

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00968

Gnomad NFE AF: 0.000133

Gnomad OTH AF: 0.0141

GnomAD2 exomes AF: 0.00473 AC: 1031 AN: 217848 AF XY: 0.00380

Gnomad AFR exome AF: 0.0752

Gnomad AMR exome AF: 0.00354

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000102

Gnomad OTH exome AF: 0.00207

GnomAD4 exome AF: 0.00215 AC: 3064 AN: 1427204 Hom.: 109 Cov.: 32 AF XY: 0.00184 AC XY: 1305 AN XY: 709086

African (AFR) AF: 0.0783 AC: 2529 AN: 32314

American (AMR) AF: 0.00405 AC: 176 AN: 43404

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25546

East Asian (EAS) AF: 0.00 AC: 0 AN: 37614

South Asian (SAS) AF: 0.000143 AC: 12 AN: 83674

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49624

Middle Eastern (MID) AF: 0.00467 AC: 25 AN: 5354

European-Non Finnish (NFE) AF: 0.0000495 AC: 54 AN: 1090896

Other (OTH) AF: 0.00456 AC: 268 AN: 58778

GnomAD4 genome AF: 0.0219 AC: 3274 AN: 149408 Hom.: 118 Cov.: 32 AF XY: 0.0204 AC XY: 1490 AN XY: 72912

African (AFR) AF: 0.0768 AC: 3102 AN: 40380

American (AMR) AF: 0.00864 AC: 130 AN: 15048

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3456

East Asian (EAS) AF: 0.00 AC: 0 AN: 4878

South Asian (SAS) AF: 0.000217 AC: 1 AN: 4612

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10280

Middle Eastern (MID) AF: 0.0104 AC: 3 AN: 288

European-Non Finnish (NFE) AF: 0.000133 AC: 9 AN: 67482

Other (OTH) AF: 0.0139 AC: 29 AN: 2084

Alfa AF: 0.000976 Hom.: 0

Bravo AF: 0.0248

ESP6500AA AF: 0.0611 AC: 267

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.00593 AC: 708

Asia WGS AF: 0.00492 AC: 17 AN: 3472

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	1	Norman-Roberts syndrome (1)
-	-	1	Norman-Roberts syndrome;C4225327:Familial temporal lobe epilepsy 7 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	19
DANN	Benign	0.93
DEOGEN2	Benign	0.060	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.59	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.3
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.53	N
REVEL	Benign	0.040
Sift	Benign	0.17	T
Sift4G	Benign	0.19	T
Polyphen		0.012	B
Vest4		0.27
MVP		0.17
MPC		0.20
ClinPred		0.0031	T
GERP RS		3.4
PromoterAI		0.068	Neutral
Varity_R		0.10
gMVP		0.64
Mutation Taster		=97/3	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: rs115165703; hg19: chr7-103629778;