5-16474669-CTTTTTTT-CTTTT

Variant names:

• chr5-16474669-CTTT-C
• rs200951949
• NM_001034850.3:c.*69_*71delAAA

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

The NM_001034850.3(RETREG1):​c.*69_*71delAAA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000757 in 1,259,686 control chromosomes in the GnomAD database, including 1 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00075 (1 hom., cov: 0)
  • Exomes 𝑓: 0.00076 (0 hom.)
• Consequence: RETREG1 NM_001034850.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• 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: Likely_benign. The variant received -4 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00075 (99/131986) while in subpopulation AFR AF = 0.00263 (93/35328). AF 95% confidence interval is 0.0022. There are 1 homozygotes in GnomAd4. There are 50 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

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.*69_*71delAAA		3_prime_UTR	Exon 9 of 9	NP_001030022.1	Q9H6L5-1
	RETREG1	NM_019000.5		c.*69_*71delAAA		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.*69_*71delAAA		3_prime_UTR	Exon 9 of 9	ENSP00000304642.9	Q9H6L5-1
	RETREG1	ENST00000399793.6	TSL:1	c.*69_*71delAAA		3_prime_UTR	Exon 7 of 7	ENSP00000382691.2	Q9H6L5-2
	RETREG1	ENST00000510362.6	TSL:1	n.*69_*71delAAA		non_coding_transcript_exon	Exon 7 of 8	ENSP00000425089.2	H0Y9U4

Frequencies

GnomAD3 genomes AF: 0.000750 AC: 99 AN: 131992 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.00264

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000760

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: 0.0000479

Gnomad OTH AF: 0.00114

GnomAD4 exome AF: 0.000757 AC: 854 AN: 1127700 Hom.: 0 AF XY: 0.000689 AC XY: 390 AN XY: 565638

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

African (AFR) AF: 0.00347 AC: 86 AN: 24816

American (AMR) AF: 0.00128 AC: 33 AN: 25838

Ashkenazi Jewish (ASJ) AF: 0.000749 AC: 15 AN: 20038

East Asian (EAS) AF: 0.000969 AC: 33 AN: 34064

South Asian (SAS) AF: 0.000744 AC: 47 AN: 63186

European-Finnish (FIN) AF: 0.000617 AC: 22 AN: 35658

Middle Eastern (MID) AF: 0.000441 AC: 2 AN: 4534

European-Non Finnish (NFE) AF: 0.000657 AC: 573 AN: 871780

Other (OTH) AF: 0.000900 AC: 43 AN: 47786

⚠️ 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: 0.000750 AC: 99 AN: 131986 Hom.: 1 Cov.: 0 AF XY: 0.000793 AC XY: 50 AN XY: 63056

African (AFR) AF: 0.00263 AC: 93 AN: 35328

American (AMR) AF: 0.0000760 AC: 1 AN: 13158

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3264

East Asian (EAS) AF: 0.00 AC: 0 AN: 4468

South Asian (SAS) AF: 0.00 AC: 0 AN: 4094

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6196

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

European-Non Finnish (NFE) AF: 0.0000479 AC: 3 AN: 62602

Other (OTH) AF: 0.00114 AC: 2 AN: 1758

Alfa AF: 0.00 Hom.: 377

ClinVar

Not reported in ClinVar

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;