Genetic Variant NM_005045.4:c.9446C>G (chr7-103490827-G-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005045.4(RELN):c.9446C>G(p.Ser3149Trp) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S3149L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

RELN
NM_005045.4 missense, splice_region

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.51

Publications

0 publications found

Variant links:

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 links:

SLC26A5-AS1 (HGNC:55680): (SLC26A5 antisense RNA 1)

SLC26A5-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RELN	NM_005045.4	MANE Select	c.9446C>G	p.Ser3149Trp	missense splice_region	Exon 59 of 65	NP_005036.2
RELN	NM_173054.3		c.9446C>G	p.Ser3149Trp	missense splice_region	Exon 59 of 64	NP_774959.1	P78509-2
SLC26A5-AS1	NR_110141.1		n.1366-13577G>C		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RELN	ENST00000428762.6	TSL:5 MANE Select	c.9446C>G	p.Ser3149Trp	missense splice_region	Exon 59 of 65	ENSP00000392423.1	P78509-1
SLC26A5-AS1	ENST00000422488.1	TSL:1	n.1366-13577G>C		intron	N/A
RELN	ENST00000424685.3	TSL:5	c.9446C>G	p.Ser3149Trp	missense splice_region	Exon 59 of 65	ENSP00000388446.3	J3KQ66

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251202

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

0.0028

BayesDel_noAF

Benign

-0.23

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.20

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.049

MetaRNN

Uncertain

0.49

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

PhyloP100

7.5

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-2.5

REVEL

Uncertain

0.30

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.0090

Polyphen

0.97

Vest4

0.48

MutPred

0.43

Loss of disorder (P = 0.0065)

MVP

0.37

MPC

1.0

ClinPred

0.93

GERP RS

4.6

Varity_R

0.15

gMVP

0.73

Mutation Taster

=70/30

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over