5-16474669-CTTTTTTT-CTTTTT

Variant names:

• chr5-16474669-CTT-C
• rs200951949
• NM_001034850.3:c.*70_*71delAA

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001034850.3(RETREG1):​c.*70_*71delAA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00568 in 1,241,146 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000030 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0063 (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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Variant has high frequency in the EAS (0.00865) population. However there is too low homozygotes in high coverage region: (expected more than 9, got 0).

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.*70_*71delAA		3_prime_UTR	Exon 9 of 9	NP_001030022.1	Q9H6L5-1
	RETREG1	NM_019000.5		c.*70_*71delAA		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.*70_*71delAA		3_prime_UTR	Exon 9 of 9	ENSP00000304642.9	Q9H6L5-1
	RETREG1	ENST00000399793.6	TSL:1	c.*70_*71delAA		3_prime_UTR	Exon 7 of 7	ENSP00000382691.2	Q9H6L5-2
	RETREG1	ENST00000510362.6	TSL:1	n.*70_*71delAA		non_coding_transcript_exon	Exon 7 of 8	ENSP00000425089.2	H0Y9U4

Frequencies

GnomAD3 genomes AF: 0.0000303 AC: 4 AN: 131980 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000283

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

GnomAD4 exome AF: 0.00635 AC: 7040 AN: 1109166 Hom.: 0 AF XY: 0.00634 AC XY: 3524 AN XY: 555932

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

African (AFR) AF: 0.00843 AC: 204 AN: 24210

American (AMR) AF: 0.00838 AC: 212 AN: 25310

Ashkenazi Jewish (ASJ) AF: 0.00716 AC: 141 AN: 19682

East Asian (EAS) AF: 0.00951 AC: 314 AN: 33014

South Asian (SAS) AF: 0.00861 AC: 530 AN: 61572

European-Finnish (FIN) AF: 0.00659 AC: 230 AN: 34880

Middle Eastern (MID) AF: 0.00559 AC: 25 AN: 4472

European-Non Finnish (NFE) AF: 0.00589 AC: 5056 AN: 859126

Other (OTH) AF: 0.00699 AC: 328 AN: 46900

⚠️ 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: 0.0000303 AC: 4 AN: 131980 Hom.: 0 Cov.: 0 AF XY: 0.0000476 AC XY: 3 AN XY: 63032

African (AFR) AF: 0.0000283 AC: 1 AN: 35278

American (AMR) AF: 0.00 AC: 0 AN: 13150

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3262

East Asian (EAS) AF: 0.00 AC: 0 AN: 4484

South Asian (SAS) AF: 0.00 AC: 0 AN: 4118

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 264

European-Non Finnish (NFE) AF: 0.0000479 AC: 3 AN: 62604

Other (OTH) AF: 0.00 AC: 0 AN: 1754

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;