7-103574266-T-C

Position:

• chr7-103574266-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2 BP4_Strong BP6 BS1

The NM_005045.4(RELN):​c.4337A>G​(p.Asn1446Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000843 in 1,614,156 control chromosomes in the GnomAD database, including 2 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1446Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00025 (1 hom., cov: 33)
  • Exomes 𝑓: 0.000067 (1 hom.)
• Consequence: RELN NM_005045.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 5.77

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), RELN. . Gene score misZ 2.2497 (greater than the threshold 3.09). Trascript score misZ 4.2638 (greater than threshold 3.09). GenCC has associacion of gene with ankylosing spondylitis, lissencephaly with cerebellar hypoplasia, Norman-Roberts syndrome, complex neurodevelopmental disorder, autosomal dominant epilepsy with auditory features, familial temporal lobe epilepsy 7.
• BP4: Computational evidence support a benign effect (MetaRNN=0.019862235).
• BP6: Variant 7-103574266-T-C is Benign according to our data. Variant chr7-103574266-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 95220.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00025 (38/152294) while in subpopulation AFR AF= 0.000867 (36/41546). AF 95% confidence interval is 0.000643. There are 1 homozygotes in gnomad4. There are 12 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RELN	NM_005045.4	c.4337A>G	p.Asn1446Ser	missense_variant	30/65	ENST00000428762.6
RELN	NM_173054.3	c.4337A>G	p.Asn1446Ser	missense_variant	30/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RELN	ENST00000428762.6	c.4337A>G	p.Asn1446Ser	missense_variant	30/65	5	NM_005045.4	P5

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152176 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000869

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000143 AC: 36 AN: 251374 Hom.: 0 AF XY: 0.000132 AC XY: 18 AN XY: 135860

Gnomad AFR exome AF: 0.00135

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000670 AC: 98 AN: 1461862 Hom.: 1 Cov.: 32 AF XY: 0.0000660 AC XY: 48 AN XY: 727238

Gnomad4 AFR exome AF: 0.00116

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000387

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.000250 AC: 38 AN: 152294 Hom.: 1 Cov.: 33 AF XY: 0.000161 AC XY: 12 AN XY: 74462

Gnomad4 AFR AF: 0.000867

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000135 Hom.: 0

Bravo AF: 0.000272

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000157 AC: 19

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Norman-Roberts syndrome;C4225327:Familial temporal lobe epilepsy 7;C4551957:Epilepsy, familial temporal lobe, 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Apr 23, 2013

- -

Norman-Roberts syndrome;C4225327:Familial temporal lobe epilepsy 7 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 27, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	14
DANN	Benign	0.96
DEOGEN2	Benign	0.062	T;.;.
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.10
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.85	T;T;T
M_CAP	Benign	0.0064	T
MetaRNN	Benign	0.020	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L;L;.
MutationTaster	Benign	0.98	D;D;D
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.53	N;N;N
REVEL	Benign	0.10
Sift	Benign	0.70	T;T;T
Sift4G	Benign	0.77	T;T;T
Polyphen		0.13	B;B;.
Vest4		0.22
MVP		0.49
MPC		0.28
ClinPred		0.024	T
GERP RS		5.5
Varity_R		0.090
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs115577014; hg19: chr7-103214713;