7-103510944-A-C

Variant names:

• chr7-103510944-A-C
• rs778861276
• NM_005045.4:c.8181T>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6 BS1

The NM_005045.4(RELN):​c.8181T>G​(p.Asp2727Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,460,304 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. D2727D) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: RELN NM_005045.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 0.326
• Publications: 0 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 -5 ACMG points.

• BP6: Variant 7-103510944-A-C is Benign according to our data. Variant chr7-103510944-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 572620.
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.00000479 (7/1460304) while in subpopulation AMR AF = 0.000157 (7/44694). AF 95% confidence interval is 0.0000729. There are 0 homozygotes in GnomAdExome4. There are 4 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. 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.8181T>G	p.Asp2727Glu	missense	Exon 51 of 65	NP_005036.2
	RELN	NM_173054.3		c.8181T>G	p.Asp2727Glu	missense	Exon 51 of 64	NP_774959.1	P78509-2
	SLC26A5-AS1	NR_110141.1		n.1487-1825A>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RELN	ENST00000428762.6	TSL:5 MANE Select	c.8181T>G	p.Asp2727Glu	missense	Exon 51 of 65	ENSP00000392423.1	P78509-1
	SLC26A5-AS1	ENST00000422488.1	TSL:1	n.1487-1825A>C		intron	N/A
	RELN	ENST00000424685.3	TSL:5	c.8181T>G	p.Asp2727Glu	missense	Exon 51 of 65	ENSP00000388446.3	J3KQ66

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 251390 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

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: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1460304 Hom.: 0 Cov.: 30 AF XY: 0.00000551 AC XY: 4 AN XY: 726592

African (AFR) AF: 0.00 AC: 0 AN: 33450

American (AMR) AF: 0.000157 AC: 7 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110612

Other (OTH) AF: 0.00 AC: 0 AN: 60338

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000247 AC: 3

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)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.053	T
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	T
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.025	D
MetaRNN	Uncertain	0.57	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.33
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.30
Sift	Benign	0.057	T
Sift4G	Uncertain	0.022	D
Polyphen		1.0	D
Vest4		0.72
MutPred		0.49		Loss of sheet (P = 0.0104)
MVP		0.73
MPC		0.95
ClinPred		0.37	T
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.48
Mutation Taster		=85/15	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: rs778861276; hg19: chr7-103151391;