17-745992-C-T

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.2051G>A(p.Arg684Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.157 in 1,613,082 control chromosomes in the GnomAD database, including 23,573 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.21 ( 3920 hom., cov: 32)

Exomes 𝑓: 0.15 ( 19653 hom. )

Consequence

GEMIN4
NM_015721.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.502

Publications

69 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=0.0039718747).

BP6

Variant 17-745992-C-T is Benign according to our data. Variant chr17-745992-C-T is described in ClinVar as Benign. ClinVar VariationId is 1185308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.319 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GEMIN4	NM_015721.3 link	c.2051G>A	p.Arg684Gln	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.2051G>A	p.Arg684Gln	missense_variant	Exon 2 of 2	1	NM_015721.3	ENSP00000321706.5		P57678
GEMIN4	ENST00000576778.1 link	c.2018G>A	p.Arg673Gln	missense_variant	Exon 1 of 1	6		ENSP00000459565.1		I3L2C7

Frequencies

GnomAD3 genomes

AF:

0.206

AC:

31356

AN:

151958

Hom.:

3906

Cov.:

show subpopulations

Gnomad AFR

AF:

0.319

Gnomad AMI

AF:

0.0395

Gnomad AMR

AF:

0.267

Gnomad ASJ

AF:

0.104

Gnomad EAS

AF:

0.332

Gnomad SAS

AF:

0.258

Gnomad FIN

AF:

0.124

Gnomad MID

AF:

0.168

Gnomad NFE

AF:

0.132

Gnomad OTH

AF:

0.204

GnomAD2 exomes

AF:

0.199

AC:

49475

AN:

248362

AF XY:

0.194

show subpopulations

Gnomad AFR exome

AF:

0.324

Gnomad AMR exome

AF:

0.325

Gnomad ASJ exome

AF:

0.111

Gnomad EAS exome

AF:

0.335

Gnomad FIN exome

AF:

0.128

Gnomad NFE exome

AF:

0.130

Gnomad OTH exome

AF:

0.171

GnomAD4 exome

AF:

0.152

AC:

222368

AN:

1461006

Hom.:

19653

Cov.:

AF XY:

0.154

AC XY:

112131

AN XY:

726800

show subpopulations

African (AFR)

AF:

0.319

AC:

10683

AN:

33476

American (AMR)

AF:

0.317

AC:

14150

AN:

44660

Ashkenazi Jewish (ASJ)

AF:

0.109

AC:

2836

AN:

26134

East Asian (EAS)

AF:

0.265

AC:

10524

AN:

39690

South Asian (SAS)

AF:

0.258

AC:

22268

AN:

86242

European-Finnish (FIN)

AF:

0.127

AC:

6729

AN:

52898

Middle Eastern (MID)

AF:

0.178

AC:

1024

AN:

5758

European-Non Finnish (NFE)

AF:

0.129

AC:

143658

AN:

1111788

Other (OTH)

AF:

0.174

AC:

10496

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

11342

22685

34027

45370

56712

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5540

11080

16620

22160

27700

<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:

0.207

AC:

31415

AN:

152076

Hom.:

3920

Cov.:

AF XY:

0.208

AC XY:

15463

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.318

AC:

13202

AN:

41470

American (AMR)

AF:

0.268

AC:

4091

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.104

AC:

362

AN:

3470

East Asian (EAS)

AF:

0.332

AC:

1699

AN:

5122

South Asian (SAS)

AF:

0.259

AC:

1248

AN:

4824

European-Finnish (FIN)

AF:

0.124

AC:

1316

AN:

10594

Middle Eastern (MID)

AF:

0.167

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.132

AC:

8965

AN:

68004

Other (OTH)

AF:

0.212

AC:

447

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

1248

2496

3743

4991

6239

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

332

664

996

1328

1660

<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:

0.159

Hom.:

9959

Bravo

AF:

0.220

TwinsUK

AF:

0.128

AC:

475

ALSPAC

AF:

0.121

AC:

468

ESP6500AA

AF:

0.304

AC:

1197

ESP6500EA

AF:

0.126

AC:

1049

ExAC

AF:

0.196

AC:

23660

Asia WGS

AF:

0.342

AC:

1185

AN:

3478

EpiCase

AF:

0.135

EpiControl

AF:

0.139

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jul 15, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 23322153) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Neurodevelopmental disorder with microcephaly, cataracts, and renal abnormalities

Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.83

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.36

(source)

DANN

Benign

0.64

DEOGEN2

Benign

0.0089

T;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.55

T;T

MetaRNN

Benign

0.0040

T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.0

N;.

PhyloP100

0.50

PrimateAI

Benign

0.23

PROVEAN

Benign

0.020

N;.

REVEL

Benign

0.011

Sift

Benign

0.58

T;.

Sift4G

Benign

0.58

T;T

Polyphen

0.37

B;.

Vest4

0.027

MPC

0.18

ClinPred

0.0021

GERP RS

0.42

Varity_R

0.014

gMVP

0.062

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