10-63610281-A-G

Position:

• chr10-63610281-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001001330.3(REEP3):​c.512A>G​(p.Gln171Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00121 in 1,582,212 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0067 (13 hom., cov: 32)
  • Exomes 𝑓: 0.00062 (14 hom.)
• Consequence: REEP3 NM_001001330.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.26

Genes affected

REEP3 (HGNC:23711): (receptor accessory protein 3) Predicted to enable microtubule binding activity. Involved in mitotic nuclear membrane reassembly. Predicted to be integral component of membrane. Predicted to be active in cytoplasmic microtubule; endoplasmic reticulum membrane; and endoplasmic reticulum tubular network. [provided by Alliance of Genome Resources, Apr 2022]

LOC105378329 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0029705167).
• BP6: Variant 10-63610281-A-G is Benign according to our data. Variant chr10-63610281-A-G is described in ClinVar as [Benign]. Clinvar id is 711535.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0067 (1020/152318) while in subpopulation AFR AF= 0.0229 (950/41568). AF 95% confidence interval is 0.0216. There are 13 homozygotes in gnomad4. There are 508 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
REEP3	NM_001001330.3	c.512A>G	p.Gln171Arg	missense_variant	6/8	ENST00000373758.5
LOC105378329	XR_001747467.3	n.411+4296T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
REEP3	ENST00000373758.5	c.512A>G	p.Gln171Arg	missense_variant	6/8	1	NM_001001330.3	P1
REEP3	ENST00000634963.1	c.*96A>G		3_prime_UTR_variant, NMD_transcript_variant	4/6	5

Frequencies

GnomAD3 genomes AF: 0.00670 AC: 1019 AN: 152200 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.0229

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00380

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: 0.00526

GnomAD3 exomes AF: 0.00167 AC: 330 AN: 197796 Hom.: 4 AF XY: 0.00132 AC XY: 139 AN XY: 105554

Gnomad AFR exome AF: 0.0242

Gnomad AMR exome AF: 0.00138

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000476

Gnomad OTH exome AF: 0.000192

GnomAD4 exome AF: 0.000623 AC: 891 AN: 1429894 Hom.: 14 Cov.: 31 AF XY: 0.000484 AC XY: 343 AN XY: 707976

Gnomad4 AFR exome AF: 0.0215

Gnomad4 AMR exome AF: 0.00145

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000243

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000247

Gnomad4 OTH exome AF: 0.00153

GnomAD4 genome AF: 0.00670 AC: 1020 AN: 152318 Hom.: 13 Cov.: 32 AF XY: 0.00682 AC XY: 508 AN XY: 74490

Gnomad4 AFR AF: 0.0229

Gnomad4 AMR AF: 0.00379

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00129 Hom.: 4

Bravo AF: 0.00775

ESP6500AA AF: 0.0216 AC: 81

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.00178 AC: 213

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	18
DANN	Benign	0.88
DEOGEN2	Benign	0.015	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	0.99	N;N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.19
Sift	Benign	0.50	T
Sift4G	Benign	0.55	T
Polyphen		0.20	B
Vest4		0.34
MVP		0.83
MPC		0.36
ClinPred		0.026	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.096
gMVP		0.35

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

Publications

LitVar

Other links and lift over

dbSNP: rs10995569; hg19: chr10-65370041;