14-59746353-T-C

Position:

• chr14-59746353-T-C

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.370A>G​(p.Thr124Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00188 in 1,614,098 control chromosomes in the GnomAD database, including 51 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (24 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (27 hom.)
• Consequence: RTN1 NM_021136.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.26

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=0.007245958).
• BP6: Variant 14-59746353-T-C is Benign according to our data. Variant chr14-59746353-T-C is described in ClinVar as [Benign]. Clinvar id is 778742.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 = 0.0101 (1543/152224) while in subpopulation AFR AF= 0.0353 (1467/41526). AF 95% confidence interval is 0.0338. There are 24 homozygotes in gnomad4. There are 721 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 24 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RTN1	NM_021136.3	c.370A>G	p.Thr124Ala	missense_variant	2/9	ENST00000267484.10	NP_066959.1
RTN1	XM_011537063.4	c.370A>G	p.Thr124Ala	missense_variant	2/4		XP_011535365.1
RTN1	XM_047431674.1	c.370A>G	p.Thr124Ala	missense_variant	2/4		XP_047287630.1
RTN1	XR_007064042.1	n.516A>G		non_coding_transcript_exon_variant	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RTN1	ENST00000267484.10	c.370A>G	p.Thr124Ala	missense_variant	2/9	1	NM_021136.3	ENSP00000267484

Frequencies

GnomAD3 genomes AF: 0.0101 AC: 1533 AN: 152106 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.0352

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00321

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: 0.0100

GnomAD3 exomes AF: 0.00282 AC: 708 AN: 251138 Hom.: 9 AF XY: 0.00178 AC XY: 242 AN XY: 135722

Gnomad AFR exome AF: 0.0390

Gnomad AMR exome AF: 0.00150

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00102 AC: 1484 AN: 1461874 Hom.: 27 Cov.: 32 AF XY: 0.000853 AC XY: 620 AN XY: 727238

Gnomad4 AFR exome AF: 0.0365

Gnomad4 AMR exome AF: 0.00170

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000306

Gnomad4 OTH exome AF: 0.00237

GnomAD4 genome AF: 0.0101 AC: 1543 AN: 152224 Hom.: 24 Cov.: 32 AF XY: 0.00969 AC XY: 721 AN XY: 74422

Gnomad4 AFR AF: 0.0353

Gnomad4 AMR AF: 0.00321

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: 0.00994

Alfa AF: 0.00658 Hom.: 12

Bravo AF: 0.0114

ESP6500AA AF: 0.0352 AC: 155

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00342 AC: 415

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

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 23, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.50
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.060	T;T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.75	T;T
MetaRNN	Benign	0.0072	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.0	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.5	N;.
REVEL	Benign	0.050
Sift	Uncertain	0.0020	D;.
Sift4G	Uncertain	0.023	D;D
Polyphen		0.94	P;.
Vest4		0.61
MVP		0.068
MPC		0.22
ClinPred		0.034	T
GERP RS		4.2
Varity_R		0.27
gMVP		0.34

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs61736371; hg19: chr14-60213071;