rs41275239

Variant names:

• chr7-103557156-G-A
• rs41275239
• NM_005045.4:c.5618C>T
• RELN p.Thr1873Ile

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_005045.4(RELN):​c.5618C>T​(p.Thr1873Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0035 in 1,610,538 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0027 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0036 (30 hom.)
• Consequence: RELN NM_005045.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:14
• Conservation: PhyloP100: 6.20
• Publications: 11 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: G2P, Labcorp Genetics (formerly Invitae), Illumina, Orphanet, Ambry Genetics
• familial temporal lobe epilepsy 7

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006139159).
• BP6: Variant 7-103557156-G-A is Benign according to our data. Variant chr7-103557156-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 167582.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00269 (410/152300) while in subpopulation SAS AF = 0.0193 (93/4818). AF 95% confidence interval is 0.0161. There are 3 homozygotes in GnomAd4. There are 216 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR,AD gene

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.5618C>T	p.Thr1873Ile	missense	Exon 38 of 65	NP_005036.2
	RELN	NM_173054.3		c.5618C>T	p.Thr1873Ile	missense	Exon 38 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.5618C>T	p.Thr1873Ile	missense	Exon 38 of 65	ENSP00000392423.1	P78509-1
	RELN	ENST00000424685.3	TSL:5	c.5618C>T	p.Thr1873Ile	missense	Exon 38 of 65	ENSP00000388446.3	J3KQ66
	RELN	ENST00000343529.9	TSL:5	c.5618C>T	p.Thr1873Ile	missense	Exon 38 of 64	ENSP00000345694.5	P78509-2

Frequencies

GnomAD3 genomes AF: 0.00270 AC: 411 AN: 152182 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00807

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0193

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00328

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00409 AC: 1026 AN: 250932 AF XY: 0.00504

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000984

Gnomad ASJ exome AF: 0.00835

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.000833

Gnomad NFE exome AF: 0.00353

Gnomad OTH exome AF: 0.00507

GnomAD4 exome AF: 0.00359 AC: 5229 AN: 1458238 Hom.: 30 Cov.: 30 AF XY: 0.00412 AC XY: 2989 AN XY: 725766

African (AFR) AF: 0.000479 AC: 16 AN: 33390

American (AMR) AF: 0.000962 AC: 43 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00888 AC: 232 AN: 26112

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39656

South Asian (SAS) AF: 0.0156 AC: 1344 AN: 86170

European-Finnish (FIN) AF: 0.000806 AC: 43 AN: 53364

Middle Eastern (MID) AF: 0.0125 AC: 72 AN: 5758

European-Non Finnish (NFE) AF: 0.00293 AC: 3245 AN: 1108804

Other (OTH) AF: 0.00387 AC: 233 AN: 60274

GnomAD4 genome AF: 0.00269 AC: 410 AN: 152300 Hom.: 3 Cov.: 32 AF XY: 0.00290 AC XY: 216 AN XY: 74478

African (AFR) AF: 0.000577 AC: 24 AN: 41568

American (AMR) AF: 0.000915 AC: 14 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00807 AC: 28 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.0193 AC: 93 AN: 4818

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10614

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00328 AC: 223 AN: 68026

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00362 Hom.: 6

Bravo AF: 0.00235

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.00442

EpiControl AF: 0.00516

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	7	not provided (7)
-	1	2	Norman-Roberts syndrome (3)
-	-	3	not specified (3)
-	-	1	Norman-Roberts syndrome;C4225327:Familial temporal lobe epilepsy 7 (1)
-	-	1	RELN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.057	T
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0061	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.67	N
PhyloP100		6.2
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.064
Sift	Benign	0.41	T
Sift4G	Benign	0.092	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.37
Mutation Taster		=99/1	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs41275239;

hg19: chr7-103197603;