Genetic Variant RETREG3:p.Pro434Leu (chr17-42581913-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_178126.4(RETREG3):c.1301C>T(p.Pro434Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,886 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 (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

RETREG3
NM_178126.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.60

Variant links:

Genes affected

RETREG3 (HGNC:27258): (reticulophagy regulator family member 3) Involved in positive regulation of neuron projection development. Part of protein-containing complex. [provided by Alliance of Genome Resources, Apr 2022]

RETREG3 links:

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ACMG classification

Classification made for transcript

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=0.2291508).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RETREG3	NM_178126.4 link	c.1301C>T	p.Pro434Leu	missense_variant	Exon 9 of 9	ENST00000309428.10	NP_835227.1	Q86VR2-1
RETREG3	XM_047435503.1 link	c.1010C>T	p.Pro337Leu	missense_variant	Exon 10 of 10		XP_047291459.1
RETREG3	NR_026697.2 link	n.1373C>T		non_coding_transcript_exon_variant	Exon 8 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RETREG3	ENST00000309428.10 link	c.1301C>T	p.Pro434Leu	missense_variant	Exon 9 of 9	1	NM_178126.4	ENSP00000309432.4		Q86VR2-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251358

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135876

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727244

show subpopulations

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 23, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1301C>T (p.P434L) alteration is located in exon 9 (coding exon 9) of the FAM134C gene. This alteration results from a C to T substitution at nucleotide position 1301, causing the proline (P) at amino acid position 434 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.30

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.035

T;T

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.92

D;D

M_CAP

Benign

0.018

MetaRNN

Benign

0.23

T;T

MetaSVM

Benign

-1.1

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.80

N;.

REVEL

Benign

0.21

Sift

Benign

0.11

T;.

Sift4G

Uncertain

0.034

D;T

Polyphen

0.90

P;.

Vest4

0.15

MutPred

0.14

Gain of helix (P = 0.0199);.;

MVP

0.68

MPC

0.32

ClinPred

0.57

GERP RS

5.9

Varity_R

0.049

gMVP

0.41

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over