chr5-16481072-C-T

Variant names:

• chr5-16481072-C-T
• rs143878016
• NM_001034850.3:c.607G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001034850.3(RETREG1):​c.607G>A​(p.Val203Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0046 in 1,611,312 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0030 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0048 (17 hom.)
• Consequence: RETREG1 NM_001034850.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.214
• Publications: 5 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011584997).
• BP6: Variant 5-16481072-C-T is Benign according to our data. Variant chr5-16481072-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 245600.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00297 (452/152070) while in subpopulation NFE AF = 0.00496 (337/67948). AF 95% confidence interval is 0.00452. There are 2 homozygotes in GnomAd4. There are 209 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.607G>A	p.Val203Met	missense	Exon 5 of 9	NP_001030022.1	Q9H6L5-1
	RETREG1	NM_019000.5		c.184G>A	p.Val62Met	missense	Exon 3 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.607G>A	p.Val203Met	missense	Exon 5 of 9	ENSP00000304642.9	Q9H6L5-1
	RETREG1	ENST00000399793.6	TSL:1	c.184G>A	p.Val62Met	missense	Exon 3 of 7	ENSP00000382691.2	Q9H6L5-2
	RETREG1	ENST00000510362.6	TSL:1	n.82G>A		non_coding_transcript_exon	Exon 3 of 8	ENSP00000425089.2	H0Y9U4

Frequencies

GnomAD3 genomes AF: 0.00297 AC: 452 AN: 151952 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000701

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00328

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00496

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00324 AC: 806 AN: 248472 AF XY: 0.00341

Gnomad AFR exome AF: 0.00110

Gnomad AMR exome AF: 0.00317

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00252

Gnomad NFE exome AF: 0.00464

Gnomad OTH exome AF: 0.00466

GnomAD4 exome AF: 0.00477 AC: 6964 AN: 1459242 Hom.: 17 Cov.: 30 AF XY: 0.00467 AC XY: 3388 AN XY: 726002

African (AFR) AF: 0.000809 AC: 27 AN: 33384

American (AMR) AF: 0.00323 AC: 144 AN: 44586

Ashkenazi Jewish (ASJ) AF: 0.000422 AC: 11 AN: 26046

East Asian (EAS) AF: 0.00 AC: 0 AN: 39640

South Asian (SAS) AF: 0.00291 AC: 251 AN: 86214

European-Finnish (FIN) AF: 0.00313 AC: 167 AN: 53308

Middle Eastern (MID) AF: 0.00244 AC: 14 AN: 5748

European-Non Finnish (NFE) AF: 0.00547 AC: 6076 AN: 1110056

Other (OTH) AF: 0.00455 AC: 274 AN: 60260

GnomAD4 genome AF: 0.00297 AC: 452 AN: 152070 Hom.: 2 Cov.: 32 AF XY: 0.00281 AC XY: 209 AN XY: 74346

African (AFR) AF: 0.000699 AC: 29 AN: 41496

American (AMR) AF: 0.00328 AC: 50 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00270 AC: 13 AN: 4822

European-Finnish (FIN) AF: 0.00151 AC: 16 AN: 10602

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

European-Non Finnish (NFE) AF: 0.00496 AC: 337 AN: 67948

Other (OTH) AF: 0.00190 AC: 4 AN: 2108

Alfa AF: 0.00403 Hom.: 42

Bravo AF: 0.00309

TwinsUK AF: 0.00674 AC: 25

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.00105 AC: 4

ESP6500EA AF: 0.00438 AC: 36

ExAC AF: 0.00334 AC: 404

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00426

EpiControl AF: 0.00445

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Neuropathy, hereditary sensory and autonomic, type 2B (2)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.51
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.023	T
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Benign	0.32	N
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.77	T
PhyloP100		0.21
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.17
Sift	Benign	0.066	T
Sift4G	Benign	0.11	T
Polyphen		1.0	D
Vest4		0.27
MVP		0.47
MPC		1.0
ClinPred		0.015	T
GERP RS		5.1
Varity_R		0.12
gMVP		0.40
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs143878016; hg19: chr5-16481181; COSMIC: COSV99063742; COSMIC: COSV99063742;