chr7-103561939-C-T

Variant names:

• chr7-103561939-C-T
• rs199553777
• NM_005045.4:c.5225G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_005045.4(RELN):​c.5225G>A​(p.Arg1742Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00036 in 1,420,866 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1742W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 28)
  • Exomes 𝑓: 0.00037 (2 hom.)
• Consequence: RELN NM_005045.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 7.36
• Publications: 7 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 -9 ACMG points.

• BP6: Variant 7-103561939-C-T is Benign according to our data. Variant chr7-103561939-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 475970.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000299 (39/130344) while in subpopulation AMR AF = 0.00142 (17/11930). AF 95% confidence interval is 0.000908. There are 0 homozygotes in GnomAd4. There are 20 alleles in the male GnomAd4 subpopulation. Median coverage is 28. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 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.5225G>A	p.Arg1742Gln	missense	Exon 35 of 65	NP_005036.2
	RELN	NM_173054.3		c.5225G>A	p.Arg1742Gln	missense	Exon 35 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.5225G>A	p.Arg1742Gln	missense	Exon 35 of 65	ENSP00000392423.1	P78509-1
	RELN	ENST00000424685.3	TSL:5	c.5225G>A	p.Arg1742Gln	missense	Exon 35 of 65	ENSP00000388446.3	J3KQ66
	RELN	ENST00000343529.9	TSL:5	c.5225G>A	p.Arg1742Gln	missense	Exon 35 of 64	ENSP00000345694.5	P78509-2

Frequencies

GnomAD3 genomes AF: 0.000299 AC: 39 AN: 130344 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.0000584

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00142

Gnomad ASJ AF: 0.000618

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000287

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000296 AC: 73 AN: 246256 AF XY: 0.000255

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000760

Gnomad ASJ exome AF: 0.000201

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000361

Gnomad OTH exome AF: 0.000670

GnomAD4 exome AF: 0.000367 AC: 473 AN: 1290522 Hom.: 2 Cov.: 39 AF XY: 0.000332 AC XY: 215 AN XY: 646878

African (AFR) AF: 0.000170 AC: 5 AN: 29448

American (AMR) AF: 0.000760 AC: 32 AN: 42088

Ashkenazi Jewish (ASJ) AF: 0.000268 AC: 6 AN: 22402

East Asian (EAS) AF: 0.0000630 AC: 2 AN: 31762

South Asian (SAS) AF: 0.0000120 AC: 1 AN: 83614

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45244

Middle Eastern (MID) AF: 0.000439 AC: 2 AN: 4554

European-Non Finnish (NFE) AF: 0.000414 AC: 406 AN: 979618

Other (OTH) AF: 0.000367 AC: 19 AN: 51792

GnomAD4 genome AF: 0.000299 AC: 39 AN: 130344 Hom.: 0 Cov.: 28 AF XY: 0.000322 AC XY: 20 AN XY: 62054

African (AFR) AF: 0.0000584 AC: 2 AN: 34260

American (AMR) AF: 0.00142 AC: 17 AN: 11930

Ashkenazi Jewish (ASJ) AF: 0.000618 AC: 2 AN: 3238

East Asian (EAS) AF: 0.00 AC: 0 AN: 4368

South Asian (SAS) AF: 0.00 AC: 0 AN: 3612

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 254

European-Non Finnish (NFE) AF: 0.000287 AC: 18 AN: 62714

Other (OTH) AF: 0.00 AC: 0 AN: 1710

Alfa AF: 0.000245 Hom.: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000255 AC: 31

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	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	Pathogenic	0.78
BayesDel_addAF	Benign	-0.092	T
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.38	T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.024	T
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PhyloP100		7.4
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.33
Sift	Benign	0.12	T
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.83
MVP		0.72
MPC		0.74
ClinPred		0.14	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.31
gMVP		0.85
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs199553777; hg19: chr7-103202386; COSMIC: COSV59008967;