Variant 17-746265-T-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_015721.3(GEMIN4):c.1778A>T(p.Glu593Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.235 in 1,613,572 control chromosomes in the GnomAD database, including 46,738 homozygotes. 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 Benign (★★).

Frequency

Genomes: 𝑓 0.19 ( 3260 hom., cov: 32)

Exomes 𝑓: 0.24 ( 43478 hom. )

Consequence

GEMIN4
NM_015721.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.0140

Variant links:

Genes affected

GEMIN4 (HGNC:15717): (gem nuclear organelle associated protein 4) The product of this gene is part of a large complex localized to the cytoplasm, nucleoli, and to discrete nuclear bodies called Gemini bodies (gems). The complex functions in spliceosomal snRNP assembly in the cytoplasm, and regenerates spliceosomes required for pre-mRNA splicing in the nucleus. The encoded protein directly interacts with a DEAD box protein and several spliceosome core proteins. Alternatively spliced transcript variants have been described, but their biological validity has not been determined. [provided by RefSeq, Jul 2008]

GEMIN4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0046203732).

BP6

Variant 17-746265-T-A is Benign according to our data. Variant chr17-746265-T-A is described in ClinVar as [Benign]. Clinvar id is 1222413.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.253 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GEMIN4	NM_015721.3 linkuse as main transcript	c.1778A>T	p.Glu593Val	missense_variant	2/2	ENST00000319004.6	NP_056536.2	P57678Q8WUM5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GEMIN4	ENST00000319004.6 linkuse as main transcript	c.1778A>T	p.Glu593Val	missense_variant	2/2	1	NM_015721.3	ENSP00000321706.5		P57678
GEMIN4	ENST00000576778.1 linkuse as main transcript	c.1745A>T	p.Glu582Val	missense_variant	1/1	6		ENSP00000459565.1		I3L2C7

Frequencies

GnomAD3 genomes

AF:

0.191

AC:

28999

AN:

152004

Hom.:

3258

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0908

Gnomad AMI

AF:

0.408

Gnomad AMR

AF:

0.159

Gnomad ASJ

AF:

0.244

Gnomad EAS

AF:

0.124

Gnomad SAS

AF:

0.219

Gnomad FIN

AF:

0.188

Gnomad MID

AF:

0.111

Gnomad NFE

AF:

0.256

Gnomad OTH

AF:

0.210

GnomAD3 exomes

AF:

0.204

AC:

50811

AN:

249018

Hom.:

5725

AF XY:

0.209

AC XY:

28211

AN XY:

135164

show subpopulations

Gnomad AFR exome

AF:

0.0907

Gnomad AMR exome

AF:

0.119

Gnomad ASJ exome

AF:

0.246

Gnomad EAS exome

AF:

0.114

Gnomad SAS exome

AF:

0.200

Gnomad FIN exome

AF:

0.193

Gnomad NFE exome

AF:

0.259

Gnomad OTH exome

AF:

0.215

GnomAD4 exome

AF:

0.239

AC:

349816

AN:

1461450

Hom.:

43478

Cov.:

AF XY:

0.238

AC XY:

173337

AN XY:

726970

show subpopulations

Gnomad4 AFR exome

AF:

0.0855

Gnomad4 AMR exome

AF:

0.125

Gnomad4 ASJ exome

AF:

0.243

Gnomad4 EAS exome

AF:

0.145

Gnomad4 SAS exome

AF:

0.194

Gnomad4 FIN exome

AF:

0.191

Gnomad4 NFE exome

AF:

0.259

Gnomad4 OTH exome

AF:

0.232

GnomAD4 genome

AF:

0.191

AC:

29005

AN:

152122

Hom.:

3260

Cov.:

AF XY:

0.189

AC XY:

14036

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.0907

Gnomad4 AMR

AF:

0.159

Gnomad4 ASJ

AF:

0.244

Gnomad4 EAS

AF:

0.124

Gnomad4 SAS

AF:

0.219

Gnomad4 FIN

AF:

0.188

Gnomad4 NFE

AF:

0.257

Gnomad4 OTH

AF:

0.208

Alfa

AF:

0.244

Hom.:

3531

Bravo

AF:

0.184

TwinsUK

AF:

0.265

AC:

984

ALSPAC

AF:

0.263

AC:

1012

ESP6500AA

AF:

0.0918

AC:

361

ESP6500EA

AF:

0.252

AC:

2103

ExAC

AF:

0.208

AC:

25111

Asia WGS

AF:

0.189

AC:

660

AN:

3478

EpiCase

AF:

0.248

EpiControl

AF:

0.251

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 28, 2020	This variant is associated with the following publications: (PMID: 22639842) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

GEMIN4-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 17, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.47

CADD

Benign

9.2

DANN

Benign

0.90

DEOGEN2

Benign

0.028

T;.

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.31

FATHMM_MKL

Benign

0.37

LIST_S2

Benign

0.51

T;T

MetaRNN

Benign

0.0046

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Uncertain

2.2

M;.

PrimateAI

Benign

0.30

PROVEAN

Benign

-1.7

N;.

REVEL

Benign

0.14

Sift

Benign

0.14

T;.

Sift4G

Benign

0.14

T;T

Polyphen

0.28

B;.

Vest4

0.16

MPC

0.24

ClinPred

0.018

GERP RS

5.5

Varity_R

0.054

gMVP

0.30

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over