rs114807343

Variant names:

• chr7-103553706-C-T
• rs114807343
• NM_005045.4:c.5923G>A

Your query was ambiguous. Multiple possible variants found:

• chr7-103553706-C-T
• chr7-103553706-C-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005045.4(RELN):​c.5923G>A​(p.Gly1975Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000501 in 1,614,100 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts 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. G1975D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0028 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00026 (2 hom.)
• Consequence: RELN NM_005045.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 7.57
• Publications: 5 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=0.014485866).
• BP6: Variant 7-103553706-C-T is Benign according to our data. Variant chr7-103553706-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 167581.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00279 (425/152272) while in subpopulation AFR AF = 0.0096 (399/41548). AF 95% confidence interval is 0.00883. There are 4 homozygotes in GnomAd4. There are 200 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 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.5923G>A	p.Gly1975Ser	missense	Exon 39 of 65	NP_005036.2
	RELN	NM_173054.3		c.5923G>A	p.Gly1975Ser	missense	Exon 39 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.5923G>A	p.Gly1975Ser	missense	Exon 39 of 65	ENSP00000392423.1	P78509-1
	RELN	ENST00000424685.3	TSL:5	c.5923G>A	p.Gly1975Ser	missense	Exon 39 of 65	ENSP00000388446.3	J3KQ66
	RELN	ENST00000343529.9	TSL:5	c.5923G>A	p.Gly1975Ser	missense	Exon 39 of 64	ENSP00000345694.5	P78509-2

Frequencies

GnomAD3 genomes AF: 0.00281 AC: 428 AN: 152154 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00963

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000669 AC: 168 AN: 251182 AF XY: 0.000567

Gnomad AFR exome AF: 0.00886

Gnomad AMR exome AF: 0.000492

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000262 AC: 383 AN: 1461828 Hom.: 2 Cov.: 32 AF XY: 0.000210 AC XY: 153 AN XY: 727218

African (AFR) AF: 0.00896 AC: 300 AN: 33480

American (AMR) AF: 0.000693 AC: 31 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111986

Other (OTH) AF: 0.000695 AC: 42 AN: 60392

GnomAD4 genome AF: 0.00279 AC: 425 AN: 152272 Hom.: 4 Cov.: 32 AF XY: 0.00269 AC XY: 200 AN XY: 74446

African (AFR) AF: 0.00960 AC: 399 AN: 41548

American (AMR) AF: 0.00144 AC: 22 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68014

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.000891 Hom.: 1

Bravo AF: 0.00320

ESP6500AA AF: 0.00794 AC: 35

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000807 AC: 98

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		7.6
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.37
Sift	Benign	0.033	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.98	D
Vest4		0.92
MVP		0.81
MPC		0.50
ClinPred		0.016	T
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.34
gMVP		0.63
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs114807343; hg19: chr7-103194153;