chr14-59746353-T-C

Variant names:

• chr14-59746353-T-C
• rs61736371
• NM_021136.3:c.370A>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 4 publications found

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

Our verdict: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 24 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021136.3. 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
	RTN1	NM_021136.3	MANE Select	c.370A>G	p.Thr124Ala	missense	Exon 2 of 9	NP_066959.1	Q16799-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RTN1	ENST00000267484.10	TSL:1 MANE Select	c.370A>G	p.Thr124Ala	missense	Exon 2 of 9	ENSP00000267484.5	Q16799-1
	RTN1	ENST00000966440.1		c.370A>G	p.Thr124Ala	missense	Exon 2 of 9	ENSP00000636499.1
	RTN1	ENST00000966441.1		c.370A>G	p.Thr124Ala	missense	Exon 2 of 9	ENSP00000636500.1

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

GnomAD2 exomes AF: 0.00282 AC: 708 AN: 251138 AF XY: 0.00178

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 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

African (AFR) AF: 0.0365 AC: 1222 AN: 33476

American (AMR) AF: 0.00170 AC: 76 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.0000306 AC: 34 AN: 1112000

Other (OTH) AF: 0.00237 AC: 143 AN: 60396

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

African (AFR) AF: 0.0353 AC: 1467 AN: 41526

American (AMR) AF: 0.00321 AC: 49 AN: 15286

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68018

Other (OTH) AF: 0.00994 AC: 21 AN: 2112

Alfa AF: 0.0111 Hom.: 25

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.0072	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		2.3
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.050
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.023	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
Mutation Taster		=89/11	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs61736371; hg19: chr14-60213071;