rs73714410

Variant names:

• chr7-103489775-C-G
• rs73714410
• NM_005045.4:c.9730G>C

Your query was ambiguous. Multiple possible variants found:

• chr7-103489775-C-G
• chr7-103489775-C-T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 4P and 5B. PP3_Strong BP6 BS1

The NM_005045.4(RELN):​c.9730G>C​(p.Gly3244Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,613,962 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. G3244S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: RELN NM_005045.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 7.36
• 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]

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

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.978
• BP6: Variant 7-103489775-C-G is Benign according to our data. Variant chr7-103489775-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 958771.
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.0000116 (17/1461788) while in subpopulation AMR AF = 0.000335 (15/44722). AF 95% confidence interval is 0.000207. There are 0 homozygotes in GnomAdExome4. There are 8 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.

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.9730G>C	p.Gly3244Arg	missense	Exon 60 of 65	NP_005036.2
	RELN	NM_173054.3		c.9730G>C	p.Gly3244Arg	missense	Exon 60 of 64	NP_774959.1	P78509-2
	SLC26A5-AS1	NR_110141.1		n.1366-14629C>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RELN	ENST00000428762.6	TSL:5 MANE Select	c.9730G>C	p.Gly3244Arg	missense	Exon 60 of 65	ENSP00000392423.1	P78509-1
	SLC26A5-AS1	ENST00000422488.1	TSL:1	n.1366-14629C>G		intron	N/A
	RELN	ENST00000424685.3	TSL:5	c.9730G>C	p.Gly3244Arg	missense	Exon 60 of 65	ENSP00000388446.3	J3KQ66

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.00

GnomAD2 exomes AF: 0.0000598 AC: 15 AN: 250968 AF XY: 0.0000516

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1461788 Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8 AN XY: 727184

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.000335 AC: 15 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111970

Other (OTH) AF: 0.0000331 AC: 2 AN: 60384

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152174 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74356

African (AFR) AF: 0.00 AC: 0 AN: 41422

American (AMR) AF: 0.0000655 AC: 1 AN: 15276

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 22

Bravo AF: 0.0000264

ExAC AF: 0.0000576 AC: 7

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;C4225327:Familial temporal lobe epilepsy 7 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Uncertain	0.091	D
BayesDel_noAF	Pathogenic	0.20
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	D
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.072	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Benign	-0.35	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		7.4
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.49
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.93
MutPred		0.94		Loss of catalytic residue at C3247 (P = 0.2292)
MVP		0.61
MPC		0.91
ClinPred		0.86	D
GERP RS		5.8
Varity_R		0.44
gMVP		0.79
Mutation Taster		=56/44	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

Other links and lift over

dbSNP: rs73714410; hg19: chr7-103130222; COSMIC: COSV99067107; COSMIC: COSV99067107;