14-59746490-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_021136.3(RTN1):c.242-9G>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00123 in 1,565,768 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0066 (14 hom., cov: 32)
  • Exomes 𝑓: 0.00065 (10 hom.)
• Consequence: RTN1 NM_021136.3 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00003851
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.24

Genes affected

RTN1 (HGNC:10467): (reticulon 1) This gene belongs to the family of reticulon encoding genes. Reticulons are associated with the endoplasmic reticulum, and are involved in neuroendocrine secretion or in membrane trafficking in neuroendocrine cells. This gene is considered to be a specific marker for neurological diseases and cancer, and is a potential molecular target for therapy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2011]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 14-59746490-C-G is Benign according to our data. Variant chr14-59746490-C-G is described in ClinVar as [Benign]. Clinvar id is 790143.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00659 (1003/152278) while in subpopulation AFR AF= 0.0234 (972/41554). AF 95% confidence interval is 0.0222. There are 14 homozygotes in gnomad4. There are 455 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 14 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RTN1	NM_021136.3	c.242-9G>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000267484.10
RTN1	XM_011537063.4	c.242-9G>C		splice_polypyrimidine_tract_variant, intron_variant
RTN1	XM_047431674.1	c.242-9G>C		splice_polypyrimidine_tract_variant, intron_variant
RTN1	XR_007064042.1	n.388-9G>C		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RTN1	ENST00000267484.10	c.242-9G>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_021136.3

Frequencies

GnomAD3 genomes AF: 0.00657 AC: 1000 AN: 152160 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.0234

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00201 AC: 406 AN: 202010 Hom.: 5 AF XY: 0.00144 AC XY: 155 AN XY: 107712

Gnomad AFR exome AF: 0.0233

Gnomad AMR exome AF: 0.00105

Gnomad ASJ exome AF: 0.000341

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000148

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000648

Gnomad OTH exome AF: 0.00101

GnomAD4 exome AF: 0.000652 AC: 921 AN: 1413490 Hom.: 10 Cov.: 32 AF XY: 0.000577 AC XY: 403 AN XY: 698580

Gnomad4 AFR exome AF: 0.0228

Gnomad4 AMR exome AF: 0.00120

Gnomad4 ASJ exome AF: 0.000132

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000143

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000211

Gnomad4 OTH exome AF: 0.00159

GnomAD4 genome AF: 0.00659 AC: 1003 AN: 152278 Hom.: 14 Cov.: 32 AF XY: 0.00611 AC XY: 455 AN XY: 74476

Gnomad4 AFR AF: 0.0234

Gnomad4 AMR AF: 0.000981

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00425

Alfa AF: 0.00385 Hom.: 1

Bravo AF: 0.00747

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jul 23, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
Cadd	Benign	17
Dann	Benign	0.53

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000039
dbscSNV1_RF	Benign	0.064

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

Publications

LitVar

Other links and lift over

dbSNP: rs112705146; hg19: chr14-60213208;