NM_001034850.3:c.18T>C

Variant names:

• chr5-16616954-A-G
• rs773314283
• NM_001034850.3:c.18T>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 2P and 11B. PM2 BP4_Strong BP6_Moderate BP7 BS1

The NM_001034850.3(RETREG1):​c.18T>C​(p.Pro6Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000396 in 1,438,148 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. P6P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000037 (0 hom.)
• Consequence: RETREG1 NM_001034850.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.593
• Publications: 0 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-AS1 (HGNC:55551): (RETREG1 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 5-16616954-A-G is Benign according to our data. Variant chr5-16616954-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 702107.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.593 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.0000373 (48/1286426) while in subpopulation AFR AF = 0.000193 (5/25910). AF 95% confidence interval is 0.0000753. There are 0 homozygotes in GnomAdExome4. There are 30 alleles in the male GnomAdExome4 subpopulation. Median coverage is 29. 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.18T>C	p.Pro6Pro	synonymous	Exon 1 of 9	NP_001030022.1	Q9H6L5-1
	RETREG1-AS1	NR_109946.1		n.561+468A>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RETREG1	ENST00000306320.10	TSL:1 MANE Select	c.18T>C	p.Pro6Pro	synonymous	Exon 1 of 9	ENSP00000304642.9	Q9H6L5-1
	RETREG1	ENST00000682229.1		c.18T>C	p.Pro6Pro	synonymous	Exon 1 of 10	ENSP00000507342.1	A0A804HJ37
	RETREG1	ENST00000682564.1		c.18T>C	p.Pro6Pro	synonymous	Exon 1 of 9	ENSP00000508099.1	A0A804HKW5

Frequencies

GnomAD3 genomes AF: 0.0000594 AC: 9 AN: 151614 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000968

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000589

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000601 AC: 4 AN: 66608 AF XY: 0.000103

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000804

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000373 AC: 48 AN: 1286426 Hom.: 0 Cov.: 29 AF XY: 0.0000474 AC XY: 30 AN XY: 632624

African (AFR) AF: 0.000193 AC: 5 AN: 25910

American (AMR) AF: 0.00 AC: 0 AN: 23330

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22018

East Asian (EAS) AF: 0.000108 AC: 3 AN: 27854

South Asian (SAS) AF: 0.000103 AC: 7 AN: 68060

European-Finnish (FIN) AF: 0.000157 AC: 5 AN: 31942

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3816

European-Non Finnish (NFE) AF: 0.0000262 AC: 27 AN: 1030474

Other (OTH) AF: 0.0000189 AC: 1 AN: 53022

GnomAD4 genome AF: 0.0000593 AC: 9 AN: 151722 Hom.: 0 Cov.: 32 AF XY: 0.0000540 AC XY: 4 AN XY: 74140

African (AFR) AF: 0.0000965 AC: 4 AN: 41444

American (AMR) AF: 0.00 AC: 0 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5122

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10424

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000589 AC: 4 AN: 67884

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000604

Asia WGS AF: 0.000292 AC: 1 AN: 3438

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
BayesDel_noAF	Benign	-0.81
CADD	Benign	6.2
DANN	Benign	0.49
PhyloP100		-0.59
PromoterAI		-0.18	Neutral
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: rs773314283; hg19: chr5-16617063; COSMIC: COSV60447271; COSMIC: COSV60447271;