NM_001034850.3:c.*70_*71dupAA

Variant names:

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

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.*70_*71dupAA 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 0.0061 (7 hom., cov: 0)
  • Exomes 𝑓: 0.034 (8 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-C-CTT is Benign according to our data. Variant chr5-16474669-C-CTT is described in ClinVar as Likely_benign. ClinVar VariationId is 1187864.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00609 (804/131950) while in subpopulation AFR AF = 0.0172 (609/35312). AF 95% confidence interval is 0.0161. There are 7 homozygotes in GnomAd4. There are 391 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 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.*70_*71dupAA		3_prime_UTR	Exon 9 of 9	NP_001030022.1	Q9H6L5-1
	RETREG1	NM_019000.5		c.*70_*71dupAA		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_*71dupAA		3_prime_UTR	Exon 9 of 9	ENSP00000304642.9	Q9H6L5-1
	RETREG1	ENST00000399793.6	TSL:1	c.*70_*71dupAA		3_prime_UTR	Exon 7 of 7	ENSP00000382691.2	Q9H6L5-2
	RETREG1	ENST00000510362.6	TSL:1	n.*70_*71dupAA		non_coding_transcript_exon	Exon 7 of 8	ENSP00000425089.2	H0Y9U4

Frequencies

GnomAD3 genomes AF: 0.00609 AC: 803 AN: 131956 Hom.: 7 Cov.: 0

Gnomad AFR AF: 0.0172

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00525

Gnomad ASJ AF: 0.00307

Gnomad EAS AF: 0.00178

Gnomad SAS AF: 0.00121

Gnomad FIN AF: 0.000161

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00147

Gnomad OTH AF: 0.00570

GnomAD4 exome AF: 0.0343 AC: 38452 AN: 1121812 Hom.: 8 Cov.: 13 AF XY: 0.0341 AC XY: 19168 AN XY: 562788

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

African (AFR) AF: 0.0240 AC: 593 AN: 24726

American (AMR) AF: 0.0286 AC: 740 AN: 25832

Ashkenazi Jewish (ASJ) AF: 0.0359 AC: 718 AN: 19996

East Asian (EAS) AF: 0.0141 AC: 481 AN: 34068

South Asian (SAS) AF: 0.0259 AC: 1637 AN: 63100

European-Finnish (FIN) AF: 0.0252 AC: 896 AN: 35562

Middle Eastern (MID) AF: 0.0300 AC: 135 AN: 4506

European-Non Finnish (NFE) AF: 0.0366 AC: 31743 AN: 866450

Other (OTH) AF: 0.0317 AC: 1509 AN: 47572

⚠️ 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: 0.00609 AC: 804 AN: 131950 Hom.: 7 Cov.: 0 AF XY: 0.00620 AC XY: 391 AN XY: 63034

African (AFR) AF: 0.0172 AC: 609 AN: 35312

American (AMR) AF: 0.00525 AC: 69 AN: 13154

Ashkenazi Jewish (ASJ) AF: 0.00307 AC: 10 AN: 3262

East Asian (EAS) AF: 0.00179 AC: 8 AN: 4468

South Asian (SAS) AF: 0.00122 AC: 5 AN: 4094

European-Finnish (FIN) AF: 0.000161 AC: 1 AN: 6194

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

European-Non Finnish (NFE) AF: 0.00147 AC: 92 AN: 62592

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

Alfa AF: 0.000895 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

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs200951949; hg19: chr5-16474778;