chr1-155247840-C-T

Variant names:

• chr1-155247840-C-T
• rs572393078
• NM_006589.3:c.1949G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006589.3(ENTREP3):​c.1949G>A​(p.Arg650His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000396 in 1,490,648 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000041 (0 hom.)
• Consequence: ENTREP3 NM_006589.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0610
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.029114068).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENTREP3	NM_006589.3	c.1949G>A	p.Arg650His	missense_variant	Exon 12 of 12	ENST00000361361.7	NP_006580.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENTREP3	ENST00000361361.7	c.1949G>A	p.Arg650His	missense_variant	Exon 12 of 12	1	NM_006589.3	ENSP00000354958.2

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152232 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000184 AC: 2 AN: 108686 AF XY: 0.0000180

Gnomad AFR exome AF: 0.000113

Gnomad AMR exome AF: 0.0000651

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000411 AC: 55 AN: 1338416 Hom.: 0 Cov.: 32 AF XY: 0.0000443 AC XY: 29 AN XY: 654036

African (AFR) AF: 0.0000336 AC: 1 AN: 29758

American (AMR) AF: 0.0000804 AC: 2 AN: 24864

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20184

East Asian (EAS) AF: 0.00 AC: 0 AN: 36590

South Asian (SAS) AF: 0.0000441 AC: 3 AN: 68002

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46894

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4842

European-Non Finnish (NFE) AF: 0.0000456 AC: 48 AN: 1052100

Other (OTH) AF: 0.0000181 AC: 1 AN: 55182

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152232 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74380

African (AFR) AF: 0.0000724 AC: 3 AN: 41460

American (AMR) AF: 0.0000654 AC: 1 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000325 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000171 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 07, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1949G>A (p.R650H) alteration is located in exon 12 (coding exon 12) of the FAM189B gene. This alteration results from a G to A substitution at nucleotide position 1949, causing the arginine (R) at amino acid position 650 to be replaced by a histidine (H). 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	0.076
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	8.3
DANN	Benign	0.96
DEOGEN2	Benign	0.0098	.;.;T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.069	N
M_CAP	Benign	0.0057	T
MetaRNN	Benign	0.029	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	.;.;N
PhyloP100		-0.061
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.72	N;N;N
REVEL	Benign	0.022
Sift	Benign	0.26	T;T;T
Sift4G	Benign	0.14	T;T;T
Polyphen		0.0050	B;.;B
Vest4		0.087
MutPred		0.20		.;.;Loss of MoRF binding (P = 0.0236);
MVP		0.14
MPC		0.10
ClinPred		0.038	T
GERP RS		1.6
Varity_R		0.027
gMVP		0.30
Mutation Taster		=98/2	polymorphism

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

dbSNP: rs572393078; hg19: chr1-155217631;