5-16616953-G-T

Variant names:

• chr5-16616953-G-T
• rs532140281
• NM_001034850.3:c.19C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001034850.3(RETREG1):​c.19C>A​(p.Pro7Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000155 in 1,286,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P7S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: RETREG1 NM_001034850.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.783
• Publications: 1 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04257694).

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.19C>A	p.Pro7Thr	missense	Exon 1 of 9	NP_001030022.1
	RETREG1-AS1	NR_109946.1		n.561+467G>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.19C>A	p.Pro7Thr	missense	Exon 1 of 9	ENSP00000304642.9
	RETREG1	ENST00000682229.1		c.19C>A	p.Pro7Thr	missense	Exon 1 of 10	ENSP00000507342.1
	RETREG1	ENST00000682564.1		c.19C>A	p.Pro7Thr	missense	Exon 1 of 9	ENSP00000508099.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000150 AC: 1 AN: 66724 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000817

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000155 AC: 2 AN: 1286858 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 632834

African (AFR) AF: 0.00 AC: 0 AN: 25924

American (AMR) AF: 0.0000856 AC: 2 AN: 23356

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22030

East Asian (EAS) AF: 0.00 AC: 0 AN: 27862

South Asian (SAS) AF: 0.00 AC: 0 AN: 68120

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31962

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1030734

Other (OTH) AF: 0.00 AC: 0 AN: 53054

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	6.7
DANN	Benign	0.88
DEOGEN2	Benign	0.0040	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.32	T
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.043	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.78
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	0.030	N
REVEL	Benign	0.010
Sift	Benign	0.064	T
Sift4G	Benign	0.26	T
Polyphen		0.0070	B
Vest4		0.14
MutPred		0.18		Gain of phosphorylation at P7 (P = 0.0092)
MVP		0.13
MPC		0.37
ClinPred		0.039	T
GERP RS		-0.63
PromoterAI		0.039	Neutral
Varity_R		0.032
gMVP		0.23
Mutation Taster		=95/5	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: rs532140281; hg19: chr5-16617062;