7-103833594-G-C

Variant names:

• chr7-103833594-G-C
• rs79471015
• NM_005045.4:c.416C>G

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.416C>G​(p.Thr139Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00312 in 1,613,960 control chromosomes in the GnomAD database, including 154 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T139I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0037 (19 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (135 hom.)
• Consequence: RELN NM_005045.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 5.70
• Publications: 9 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: Illumina, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, G2P, PanelApp Australia
• 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=0.0037332475).
• BP6: Variant 7-103833594-G-C is Benign according to our data. Variant chr7-103833594-G-C is described in ClinVar as Benign. ClinVar VariationId is 130121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0554 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RELN	NM_005045.4	MANE Select	c.416C>G	p.Thr139Ser	missense	Exon 3 of 65	NP_005036.2
	RELN	NM_173054.3		c.416C>G	p.Thr139Ser	missense	Exon 3 of 64	NP_774959.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RELN	ENST00000428762.6	TSL:5 MANE Select	c.416C>G	p.Thr139Ser	missense	Exon 3 of 65	ENSP00000392423.1
	RELN	ENST00000424685.3	TSL:5	c.416C>G	p.Thr139Ser	missense	Exon 3 of 65	ENSP00000388446.3
	RELN	ENST00000343529.9	TSL:5	c.416C>G	p.Thr139Ser	missense	Exon 3 of 64	ENSP00000345694.5

Frequencies

GnomAD3 genomes AF: 0.00371 AC: 565 AN: 152170 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.000652

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0118

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.0610

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00833 AC: 2094 AN: 251248 AF XY: 0.00693

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.0242

Gnomad ASJ exome AF: 0.000695

Gnomad EAS exome AF: 0.0630

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000308

Gnomad OTH exome AF: 0.00310

GnomAD4 exome AF: 0.00306 AC: 4476 AN: 1461672 Hom.: 135 Cov.: 31 AF XY: 0.00290 AC XY: 2110 AN XY: 727164

African (AFR) AF: 0.000448 AC: 15 AN: 33478

American (AMR) AF: 0.0224 AC: 1000 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000957 AC: 25 AN: 26128

East Asian (EAS) AF: 0.0732 AC: 2906 AN: 39678

South Asian (SAS) AF: 0.000916 AC: 79 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5764

European-Non Finnish (NFE) AF: 0.000263 AC: 292 AN: 1111846

Other (OTH) AF: 0.00253 AC: 153 AN: 60388

GnomAD4 genome AF: 0.00370 AC: 563 AN: 152288 Hom.: 19 Cov.: 32 AF XY: 0.00389 AC XY: 290 AN XY: 74462

African (AFR) AF: 0.000650 AC: 27 AN: 41550

American (AMR) AF: 0.0118 AC: 180 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.0610 AC: 315 AN: 5168

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 68040

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00272 Hom.: 9

Bravo AF: 0.00516

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00746 AC: 906

Asia WGS AF: 0.0240 AC: 82 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Norman-Roberts syndrome (1)
-	-	1	Norman-Roberts syndrome;C4225327:Familial temporal lobe epilepsy 7 (1)
-	-	1	Norman-Roberts syndrome;C4225327:Familial temporal lobe epilepsy 7;CN030884:Epilepsy, familial temporal lobe, 1 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.51
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.060	T
Eigen	Benign	-0.042
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0037	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.40	N
PhyloP100		5.7
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.83	N
REVEL	Benign	0.074
Sift	Benign	0.099	T
Sift4G	Benign	0.49	T
Polyphen		0.074	B
Vest4		0.35
MutPred		0.61		Loss of sheet (P = 0.0315)
MVP		0.34
MPC		0.21
ClinPred		0.012	T
GERP RS		5.3
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		3.7
Varity_R		0.16
gMVP		0.29
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: rs79471015; hg19: chr7-103474041; COSMIC: COSV58991896;