NM_015307.2:c.1357G>T

Variant names:

• chr15-29123602-C-A
• NM_015307.2:c.1357G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015307.2(ENTREP2):​c.1357G>T​(p.Gly453Trp) 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. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G453E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ENTREP2 NM_015307.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.391
• Publications: 0 publications found

Genes affected

ENTREP2 (HGNC:29075): (endosomal transmembrane epsin interactor 2) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19668233).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENTREP2	NM_015307.2	c.1357G>T	p.Gly453Trp	missense_variant	Exon 11 of 11	ENST00000261275.5	NP_056122.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENTREP2	ENST00000261275.5	c.1357G>T	p.Gly453Trp	missense_variant	Exon 11 of 11	5	NM_015307.2	ENSP00000261275.4
ENTREP2	ENST00000560021.1	n.1093G>T		non_coding_transcript_exon_variant	Exon 8 of 8	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 27, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1357G>T (p.G453W) alteration is located in exon 11 (coding exon 11) of the FAM189A1 gene. This alteration results from a G to T substitution at nucleotide position 1357, causing the glycine (G) at amino acid position 453 to be replaced by a tryptophan (W). 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	0.13
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.091	T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.39
PrimateAI	Benign	0.27	T
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.065
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.020	D
Polyphen		0.99	D
Vest4		0.22
MutPred		0.27		Gain of solvent accessibility (P = 0.0062);
MVP		0.14
ClinPred		0.80	D
GERP RS		1.4
Varity_R		0.099
gMVP		0.11

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

Other links and lift over

hg19: chr15-29415805;