chr14-59745908-C-T

Position:

• chr14-59745908-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_021136.3(RTN1):​c.815G>A​(p.Arg272His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00214 in 1,613,960 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (31 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (32 hom.)
• Consequence: RTN1 NM_021136.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.111

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0024955273).
• BP6: Variant 14-59745908-C-T is Benign according to our data. Variant chr14-59745908-C-T is described in ClinVar as [Benign]. Clinvar id is 708579.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0116 (1761/152170) while in subpopulation AFR AF= 0.0403 (1673/41508). AF 95% confidence interval is 0.0387. There are 31 homozygotes in gnomad4. There are 790 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 31 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RTN1	NM_021136.3	c.815G>A	p.Arg272His	missense_variant	2/9	ENST00000267484.10	NP_066959.1
RTN1	XM_011537063.4	c.815G>A	p.Arg272His	missense_variant	2/4		XP_011535365.1
RTN1	XM_047431674.1	c.815G>A	p.Arg272His	missense_variant	2/4		XP_047287630.1
RTN1	XR_007064042.1	n.961G>A		non_coding_transcript_exon_variant	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RTN1	ENST00000267484.10	c.815G>A	p.Arg272His	missense_variant	2/9	1	NM_021136.3	ENSP00000267484

Frequencies

GnomAD3 genomes AF: 0.0116 AC: 1759 AN: 152052 Hom.: 31 Cov.: 32

Gnomad AFR AF: 0.0404

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00465

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: 0.0000882

Gnomad OTH AF: 0.00525

GnomAD3 exomes AF: 0.00304 AC: 764 AN: 251154 Hom.: 13 AF XY: 0.00213 AC XY: 289 AN XY: 135736

Gnomad AFR exome AF: 0.0421

Gnomad AMR exome AF: 0.00182

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00115 AC: 1687 AN: 1461790 Hom.: 32 Cov.: 32 AF XY: 0.000921 AC XY: 670 AN XY: 727198

Gnomad4 AFR exome AF: 0.0419

Gnomad4 AMR exome AF: 0.00208

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.00260

GnomAD4 genome AF: 0.0116 AC: 1761 AN: 152170 Hom.: 31 Cov.: 32 AF XY: 0.0106 AC XY: 790 AN XY: 74404

Gnomad4 AFR AF: 0.0403

Gnomad4 AMR AF: 0.00464

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00198 Hom.: 7

Bravo AF: 0.0132

ESP6500AA AF: 0.0397 AC: 175

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00365 AC: 443

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 15, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.026
DANN	Benign	0.25
DEOGEN2	Benign	0.0035	T;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0063	N
LIST_S2	Benign	0.54	T;T
MetaRNN	Benign	0.0025	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-1.6	N;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	1.4	N;.
REVEL	Benign	0.027
Sift	Benign	0.86	T;.
Sift4G	Benign	0.19	T;T
Polyphen		0.0	B;.
Vest4		0.12
MVP		0.043
MPC		0.13
ClinPred		0.0061	T
GERP RS		-4.0
Varity_R		0.018
gMVP		0.090

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs77180956; hg19: chr14-60212626; COSMIC: COSV99032311;