5-16616966-C-T

Variant names:

• chr5-16616966-C-T
• rs750740230
• NM_001034850.3:c.6G>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP7

The NM_001034850.3(RETREG1):​c.6G>A​(p.Ala2Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,429,166 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 Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A2A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 7.8e-7 (0 hom.)
• Consequence: RETREG1 NM_001034850.3 synonymous
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.16
• 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: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP7: Synonymous conserved (PhyloP=1.16 with no splicing effect.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RETREG1	NM_001034850.3	MANE Select	c.6G>A	p.Ala2Ala	synonymous	Exon 1 of 9	NP_001030022.1
	RETREG1-AS1	NR_109946.1		n.561+480C>T		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RETREG1	ENST00000306320.10	TSL:1 MANE Select	c.6G>A	p.Ala2Ala	synonymous	Exon 1 of 9	ENSP00000304642.9
	RETREG1	ENST00000682229.1		c.6G>A	p.Ala2Ala	synonymous	Exon 1 of 10	ENSP00000507342.1
	RETREG1	ENST00000682564.1		c.6G>A	p.Ala2Ala	synonymous	Exon 1 of 9	ENSP00000508099.1

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151688 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 7.83e-7 AC: 1 AN: 1277478 Hom.: 0 Cov.: 29 AF XY: 0.00000159 AC XY: 1 AN XY: 627642

African (AFR) AF: 0.00 AC: 0 AN: 25726

American (AMR) AF: 0.00 AC: 0 AN: 22396

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21524

East Asian (EAS) AF: 0.00 AC: 0 AN: 27542

South Asian (SAS) AF: 0.00 AC: 0 AN: 66390

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31640

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3766

European-Non Finnish (NFE) AF: 9.75e-7 AC: 1 AN: 1025920

Other (OTH) AF: 0.00 AC: 0 AN: 52574

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151688 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74066

African (AFR) AF: 0.00 AC: 0 AN: 41376

American (AMR) AF: 0.00 AC: 0 AN: 15230

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67908

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Neuropathy, hereditary sensory and autonomic, type 2B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	17
DANN	Benign	0.90
PhyloP100		1.2
PromoterAI		-0.49	Neutral

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: rs750740230; hg19: chr5-16617075;