5-16474669-CTTTTTTT-CTTTTTT

Variant names:

• chr5-16474669-CT-C
• rs200951949
• NM_001034850.3:c.*71delA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_001034850.3(RETREG1):​c.*71delA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0054 (6 hom., cov: 0)
  • Exomes 𝑓: 0.081 (1 hom.)
• Consequence: RETREG1 NM_001034850.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.728
• Publications: 2 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):

• hereditary sensory and autonomic neuropathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• 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

ENSG00000289112 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 5-16474669-CT-C is Benign according to our data. Variant chr5-16474669-CT-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1199642.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00541 (714/131958) while in subpopulation EAS AF = 0.0271 (121/4464). AF 95% confidence interval is 0.0232. There are 6 homozygotes in GnomAd4. There are 345 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RETREG1	NM_001034850.3	MANE Select	c.*71delA		3_prime_UTR	Exon 9 of 9	NP_001030022.1	Q9H6L5-1
	RETREG1	NM_019000.5		c.*71delA		3_prime_UTR	Exon 7 of 7	NP_061873.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RETREG1	ENST00000306320.10	TSL:1 MANE Select	c.*71delA		3_prime_UTR	Exon 9 of 9	ENSP00000304642.9	Q9H6L5-1
	RETREG1	ENST00000399793.6	TSL:1	c.*71delA		3_prime_UTR	Exon 7 of 7	ENSP00000382691.2	Q9H6L5-2
	RETREG1	ENST00000510362.6	TSL:1	n.*71delA		non_coding_transcript_exon	Exon 7 of 8	ENSP00000425089.2	H0Y9U4

Frequencies

GnomAD3 genomes AF: 0.00540 AC: 712 AN: 131964 Hom.: 6 Cov.: 0

Gnomad AFR AF: 0.00998

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00297

Gnomad ASJ AF: 0.00981

Gnomad EAS AF: 0.0270

Gnomad SAS AF: 0.00729

Gnomad FIN AF: 0.00129

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00193

Gnomad OTH AF: 0.00513

GnomAD4 exome AF: 0.0808 AC: 88396 AN: 1094518 Hom.: 1 Cov.: 13 AF XY: 0.0814 AC XY: 44622 AN XY: 548194

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.135 AC: 3181 AN: 23620

American (AMR) AF: 0.0978 AC: 2429 AN: 24830

Ashkenazi Jewish (ASJ) AF: 0.0908 AC: 1754 AN: 19326

East Asian (EAS) AF: 0.150 AC: 4820 AN: 32038

South Asian (SAS) AF: 0.105 AC: 6337 AN: 60624

European-Finnish (FIN) AF: 0.0836 AC: 2857 AN: 34190

Middle Eastern (MID) AF: 0.0632 AC: 277 AN: 4386

European-Non Finnish (NFE) AF: 0.0740 AC: 62846 AN: 849306

Other (OTH) AF: 0.0843 AC: 3895 AN: 46198

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00541 AC: 714 AN: 131958 Hom.: 6 Cov.: 0 AF XY: 0.00547 AC XY: 345 AN XY: 63032

African (AFR) AF: 0.0100 AC: 354 AN: 35326

American (AMR) AF: 0.00289 AC: 38 AN: 13156

Ashkenazi Jewish (ASJ) AF: 0.00981 AC: 32 AN: 3262

East Asian (EAS) AF: 0.0271 AC: 121 AN: 4464

South Asian (SAS) AF: 0.00733 AC: 30 AN: 4094

European-Finnish (FIN) AF: 0.00129 AC: 8 AN: 6198

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 248

European-Non Finnish (NFE) AF: 0.00193 AC: 121 AN: 62582

Other (OTH) AF: 0.00569 AC: 10 AN: 1758

Alfa AF: 0.00 Hom.: 377

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.73
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: rs200951949; hg19: chr5-16474778;