rs4968104

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 14/21 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

Publications

46 publications found

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 Gene-Disease associations (from GenCC):

neurodevelopmental disorder with microcephaly, cataracts, and renal abnormalities
Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

GEMIN4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
GEMIN4	NM_015721.3 link	c.1778A>T	p.Glu593Val	missense_variant	Exon 2 of 2	ENST00000319004.6	NP_056536.2	P57678Q8WUM5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GEMIN4	ENST00000319004.6 link	c.1778A>T	p.Glu593Val	missense_variant	Exon 2 of 2	1	NM_015721.3	ENSP00000321706.5		P57678
GEMIN4	ENST00000576778.1 link	c.1745A>T	p.Glu582Val	missense_variant	Exon 1 of 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

GnomAD2 exomes

AF:

0.204

AC:

50811

AN:

249018

AF XY:

0.209

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 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

African (AFR)

AF:

0.0855

AC:

2864

AN:

33480

American (AMR)

AF:

0.125

AC:

5599

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.243

AC:

6361

AN:

26136

East Asian (EAS)

AF:

0.145

AC:

5747

AN:

39700

South Asian (SAS)

AF:

0.194

AC:

16763

AN:

86258

European-Finnish (FIN)

AF:

0.191

AC:

10161

AN:

53170

Middle Eastern (MID)

AF:

0.146

AC:

840

AN:

5768

European-Non Finnish (NFE)

AF:

0.259

AC:

287466

AN:

1111844

Other (OTH)

AF:

0.232

AC:

14015

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

19244

38487

57731

76974

96218

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9490

18980

28470

37960

47450

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.191

AC:

29005

AN:

152122

Hom.:

3260

Cov.:

AF XY:

0.189

AC XY:

14036

AN XY:

74362

show subpopulations

African (AFR)

AF:

0.0907

AC:

3765

AN:

41526

American (AMR)

AF:

0.159

AC:

2425

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.244

AC:

846

AN:

3472

East Asian (EAS)

AF:

0.124

AC:

642

AN:

5168

South Asian (SAS)

AF:

0.219

AC:

1055

AN:

4822

European-Finnish (FIN)

AF:

0.188

AC:

1991

AN:

10572

Middle Eastern (MID)

AF:

0.112

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.257

AC:

17436

AN:

67974

Other (OTH)

AF:

0.208

AC:

440

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1176

2352

3527

4703

5879

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

314

628

942

1256

1570

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Apr 28, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 22639842) -

GEMIN4-related disorder

Benign:1

Oct 17, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

(source)

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;.

PhyloP100

0.014

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

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over