5-16565783-C-G

Variant names:

• chr5-16565783-C-G
• NM_001034850.3:c.438G>C
• RETREG1 p.Leu146Phe

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001034850.3(RETREG1):​c.438G>C​(p.Leu146Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L146L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RETREG1 NM_001034850.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.451
• 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 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28234965).

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.438G>C	p.Leu146Phe	missense	Exon 3 of 9	NP_001030022.1	Q9H6L5-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RETREG1	ENST00000306320.10	TSL:1 MANE Select	c.438G>C	p.Leu146Phe	missense	Exon 3 of 9	ENSP00000304642.9	Q9H6L5-1
	RETREG1	ENST00000682229.1		c.438G>C	p.Leu146Phe	missense	Exon 3 of 10	ENSP00000507342.1	A0A804HJ37
	RETREG1	ENST00000682564.1		c.438G>C	p.Leu146Phe	missense	Exon 3 of 9	ENSP00000508099.1	A0A804HKW5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.044	T
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.21
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.83	T
PhyloP100		-0.45
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.20
Sift	Benign	0.16	T
Sift4G	Benign	0.15	T
Varity_R		0.092
gMVP		0.092
Mutation Taster		=76/24	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

hg19: chr5-16565892;