chr1-155250395-C-A

Variant names:

• chr1-155250395-C-A
• rs1327518406
• NM_006589.3:c.1391G>T

Variant summary

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

The NM_006589.3(ENTREP3):​c.1391G>T​(p.Ser464Ile) 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. 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. S464G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000016 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ENTREP3 NM_006589.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.813

Genes affected

ENTREP3 (HGNC:1233): (endosomal transmembrane epsin interactor 3) This gene is located near the gene for the lysosomal enzyme glucosylceramidase; a deficiency in this enzyme is associated with Gaucher disease. The encoded protein has been identified as a potential binding partner of a WW domain-containing protein which is involved in apoptosis and tumor suppression. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENTREP3	NM_006589.3	c.1391G>T	p.Ser464Ile	missense_variant	Exon 9 of 12	ENST00000361361.7	NP_006580.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENTREP3	ENST00000361361.7	c.1391G>T	p.Ser464Ile	missense_variant	Exon 9 of 12	1	NM_006589.3	ENSP00000354958.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000164 AC: 2 AN: 1219390 Hom.: 0 Cov.: 39 AF XY: 0.00000165 AC XY: 1 AN XY: 605392

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000330

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: 0.00000107

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000302

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 15, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1391G>T (p.S464I) alteration is located in exon 9 (coding exon 9) of the FAM189B gene. This alteration results from a G to T substitution at nucleotide position 1391, causing the serine (S) at amino acid position 464 to be replaced by an isoleucine (I). 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	Pathogenic	0.86
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0099	.;.;T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Benign	0.76	D
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.25	T;T;T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	0.81	.;.;L
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-0.21	N;N;N
REVEL	Benign	0.12
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.026	D;D;D
Polyphen		0.99	D;.;D
Vest4		0.44
MutPred		0.23		.;.;Loss of phosphorylation at S464 (P = 0.001);
MVP		0.28
MPC		3.1
ClinPred		0.79	D
GERP RS		4.3
Varity_R		0.22
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.46		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.46		Position offset: -7

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1327518406; hg19: chr1-155220186;