5-16565783-C-T

Variant names:

• chr5-16565783-C-T
• rs61741225
• NM_001034850.3:c.438G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001034850.3(RETREG1):​c.438G>A​(p.Leu146Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00171 in 1,613,908 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0086 (12 hom., cov: 32)
  • Exomes 𝑓: 0.00099 (28 hom.)
• Consequence: RETREG1 NM_001034850.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.451
• Publications: 3 publications found

Genes affected

RETREG1 (HGNC:25964): (reticulophagy regulator 1) The protein encoded by this gene is a cis-Golgi transmembrane protein that may be necessary for the long-term survival of nociceptive and autonomic ganglion neurons. Mutations in this gene are a cause of hereditary sensory and autonomic neuropathy type IIB (HSAN IIB), and this gene may also play a role in susceptibility to vascular dementia. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Nov 2011]

RETREG1 Gene-Disease associations (from GenCC):

• neuropathy, hereditary sensory and autonomic, type 2B

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• hereditary sensory and autonomic neuropathy type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.3).
• BP6: Variant 5-16565783-C-T is Benign according to our data. Variant chr5-16565783-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 352694.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.451 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00861 (1311/152288) while in subpopulation AFR AF = 0.0294 (1222/41558). AF 95% confidence interval is 0.028. There are 12 homozygotes in GnomAd4. There are 653 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001034850.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RETREG1	NM_001034850.3	MANE Select	c.438G>A	p.Leu146Leu	synonymous	Exon 3 of 9	NP_001030022.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RETREG1	ENST00000306320.10	TSL:1 MANE Select	c.438G>A	p.Leu146Leu	synonymous	Exon 3 of 9	ENSP00000304642.9
	RETREG1	ENST00000682229.1		c.438G>A	p.Leu146Leu	synonymous	Exon 3 of 10	ENSP00000507342.1
	RETREG1	ENST00000682564.1		c.438G>A	p.Leu146Leu	synonymous	Exon 3 of 9	ENSP00000508099.1

Frequencies

GnomAD3 genomes AF: 0.00853 AC: 1298 AN: 152170 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.0292

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.0105

GnomAD2 exomes AF: 0.00219 AC: 545 AN: 248870 AF XY: 0.00182

Gnomad AFR exome AF: 0.0304

Gnomad AMR exome AF: 0.00160

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000797

Gnomad OTH exome AF: 0.00149

GnomAD4 exome AF: 0.000987 AC: 1442 AN: 1461620 Hom.: 28 Cov.: 31 AF XY: 0.000869 AC XY: 632 AN XY: 727080

African (AFR) AF: 0.0343 AC: 1149 AN: 33468

American (AMR) AF: 0.00181 AC: 81 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86142

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

Middle Eastern (MID) AF: 0.00295 AC: 17 AN: 5768

European-Non Finnish (NFE) AF: 0.0000252 AC: 28 AN: 1111964

Other (OTH) AF: 0.00257 AC: 155 AN: 60388

GnomAD4 genome AF: 0.00861 AC: 1311 AN: 152288 Hom.: 12 Cov.: 32 AF XY: 0.00877 AC XY: 653 AN XY: 74466

African (AFR) AF: 0.0294 AC: 1222 AN: 41558

American (AMR) AF: 0.00373 AC: 57 AN: 15302

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68016

Other (OTH) AF: 0.0104 AC: 22 AN: 2114

Alfa AF: 0.00391 Hom.: 3

Bravo AF: 0.0101

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Neuropathy, hereditary sensory and autonomic, type 2B (2)
-	-	2	not provided (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.30
CADD	Benign	7.9
DANN	Benign	0.74
PhyloP100		-0.45
Mutation Taster		=100/0	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: rs61741225; hg19: chr5-16565892;