15-29123412-C-A

Position:

• chr15-29123412-C-A

Variant summary

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

The NM_015307.2(ENTREP2):​c.1547G>T​(p.Arg516Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,398,602 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: ENTREP2 NM_015307.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.392

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

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=0.24396923).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ENTREP2	NM_015307.2	c.1547G>T	p.Arg516Leu	missense_variant	11/11	ENST00000261275.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ENTREP2	ENST00000261275.5	c.1547G>T	p.Arg516Leu	missense_variant	11/11	5	NM_015307.2	P1
ENTREP2	ENST00000560021.1	n.1283G>T		non_coding_transcript_exon_variant	8/8	1

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1398602 Hom.: 0 Cov.: 72 AF XY: 0.00000145 AC XY: 1 AN XY: 689670

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: 9.27e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 35

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

Mar 30, 2024

The c.1547G>T (p.R516L) 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 1547, causing the arginine (R) at amino acid position 516 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	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	2.1
DANN	Benign	0.97
DEOGEN2	Benign	0.11	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.45	T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.21	T
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.13
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.025	D
Polyphen		0.53	P
Vest4		0.47
MutPred		0.51		Loss of catalytic residue at R516 (P = 0.0612);
MVP		0.092
ClinPred		0.75	D
GERP RS		-1.8
Varity_R		0.072
gMVP		0.21

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: rs577739862; hg19: chr15-29415615;