17-42581928-C-G

Variant summary

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

The NM_178126.4(RETREG3):c.1286G>C(p.Gly429Ala) 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. 14/20 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)
• Consequence: RETREG3 NM_178126.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.29

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]

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=0.08004132).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RETREG3	NM_178126.4	c.1286G>C	p.Gly429Ala	missense_variant	9/9	ENST00000309428.10
RETREG3	XM_047435503.1	c.995G>C	p.Gly332Ala	missense_variant	10/10
RETREG3	NR_026697.2	n.1358G>C		non_coding_transcript_exon_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RETREG3	ENST00000309428.10	c.1286G>C	p.Gly429Ala	missense_variant	9/9	1	NM_178126.4	P1
RETREG3	ENST00000585894.5	c.995G>C	p.Gly332Ala	missense_variant	9/9	1
RETREG3	ENST00000586870.5	c.*853G>C		3_prime_UTR_variant, NMD_transcript_variant	8/8	2
RETREG3	ENST00000589797.5	c.*1438G>C		3_prime_UTR_variant, NMD_transcript_variant	8/8	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 20, 2022

The c.1286G>C (p.G429A) alteration is located in exon 9 (coding exon 9) of the FAM134C gene. This alteration results from a G to C substitution at nucleotide position 1286, causing the glycine (G) at amino acid position 429 to be replaced by an alanine (A). 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	0.091
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	17
Dann	Benign	0.94
DEOGEN2	Benign	0.016	T;T
Eigen	Benign	-0.15
Eigen_PC	Benign	0.076
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.70	T;T
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.080	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.98	D;D;D
PrimateAI	Benign	0.42	T
PROVEAN	Benign	0.24	N;.
REVEL	Benign	0.094
Sift	Benign	0.47	T;.
Sift4G	Benign	0.81	T;T
Polyphen		0.11	B;.
Vest4		0.031
MutPred		0.13		Gain of helix (P = 0.0425);.;
MVP		0.67
MPC		0.15
ClinPred		0.15	T
GERP RS		5.9
Varity_R		0.019
gMVP		0.15

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: rs965082838; hg19: chr17-40733946;