chr19-1491276-G-A

Position:

• chr19-1491276-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_138393.4(REEP6):​c.7G>A​(p.Gly3Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000381 in 1,311,714 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000038 (0 hom.)
• Consequence: REEP6 NM_138393.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.477

Genes affected

REEP6 (HGNC:30078): (receptor accessory protein 6) The protein encoded by this gene may be involved in the transport of receptors from the endoplasmic reticulum (ER) to the cell surface. The encoded protein may also play a role in regulating ER membrane structure. This gene is required for the proper development of retinal rods and photoreceptors, with defects in this gene being associated with retinitis pigmentosa 77. [provided by RefSeq, May 2017]

REEP6 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.096992135).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
REEP6	NM_001329556.3	c.7G>A	p.Gly3Ser	missense_variant	1/6	ENST00000395479.10	NP_001316485.1
REEP6	NM_138393.4	c.7G>A	p.Gly3Ser	missense_variant	1/5	ENST00000233596.8	NP_612402.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
REEP6	ENST00000395479.10	c.7G>A	p.Gly3Ser	missense_variant	1/6	3	NM_001329556.3	ENSP00000378861.5
REEP6	ENST00000233596.8	c.7G>A	p.Gly3Ser	missense_variant	1/5	1	NM_138393.4	ENSP00000233596.2
REEP6	ENST00000591735.2	n.111G>A		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000381 AC: 5 AN: 1311714 Hom.: 0 Cov.: 30 AF XY: 0.00000620 AC XY: 4 AN XY: 644980

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000482

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 25, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 1017464). This variant has not been reported in the literature in individuals affected with REEP6-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 3 of the REEP6 protein (p.Gly3Ser). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	15
DANN	Uncertain	0.98
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.57	T
M_CAP	Uncertain	0.097	D
MetaRNN	Benign	0.097	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.66	N
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	0.050	N
REVEL	Benign	0.13
Sift	Benign	0.76	T
Sift4G	Benign	0.89	T
Vest4		0.083
MutPred		0.15		Gain of phosphorylation at G3 (P = 0.0561);
MVP		0.72
MPC		0.24
ClinPred		0.069	T
GERP RS		0.23
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.12

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

Publications

LitVar

Other links and lift over

dbSNP: rs1314788573; hg19: chr19-1491275;