17-42592072-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_178126.4(RETREG3):c.330C>G(p.Ile110Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,460,310 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: 0.0000034 (0 hom.)
• Consequence: RETREG3 NM_178126.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.15

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29646447).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RETREG3	NM_178126.4	c.330C>G	p.Ile110Met	missense_variant	2/9	ENST00000309428.10
RETREG3	XM_047435503.1	c.39C>G	p.Ile13Met	missense_variant	3/10
RETREG3	NR_026697.2	n.433C>G		non_coding_transcript_exon_variant	2/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RETREG3	ENST00000309428.10	c.330C>G	p.Ile110Met	missense_variant	2/9	1	NM_178126.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 249758 Hom.: 0 AF XY: 0.00000741 AC XY: 1 AN XY: 134944

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1460310 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726388

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

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

Nov 16, 2021

The c.330C>G (p.I110M) alteration is located in exon 2 (coding exon 2) of the FAM134C gene. This alteration results from a C to G substitution at nucleotide position 330, causing the isoleucine (I) at amino acid position 110 to be replaced by a methionine (M). 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	Uncertain	0.45
BayesDel_addAF	Uncertain	0.060	T
BayesDel_noAF	Benign	-0.15
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.087	T;T;T;T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.92	D;D;D;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.30	T;T;T;T
MetaSVM	Benign	-0.83	T
MutationTaster	Benign	0.98	D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.0	N;.;.;.
REVEL	Benign	0.26
Sift	Uncertain	0.0070	D;.;.;.
Sift4G	Uncertain	0.034	D;T;T;D
Polyphen		1.0	D;.;.;.
Vest4		0.62
MutPred		0.39		Loss of methylation at K109 (P = 0.0263);.;.;.;
MVP		0.71
MPC		0.58
ClinPred		0.80	D
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22
gMVP		0.77

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: rs1327444902; hg19: chr17-40744090; COSMIC: COSV105175866; COSMIC: COSV105175866;