17-746307-G-C

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.1736C>G(p.Ala579Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.588 in 1,613,454 control chromosomes in the GnomAD database, including 283,902 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.66 ( 34134 hom., cov: 32)

Exomes 𝑓: 0.58 ( 249768 hom. )

Consequence

GEMIN4
NM_015721.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 9.85

Publications

51 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=1.4544598E-6).

BP6

Variant 17-746307-G-C is Benign according to our data. Variant chr17-746307-G-C is described in ClinVar as Benign. ClinVar VariationId is 1185309.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.827 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015721.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GEMIN4	NM_015721.3	MANE Select	c.1736C>G	p.Ala579Gly	missense	Exon 2 of 2	NP_056536.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GEMIN4	ENST00000319004.6	TSL:1 MANE Select	c.1736C>G	p.Ala579Gly	missense	Exon 2 of 2	ENSP00000321706.5
	GEMIN4	ENST00000576778.1	TSL:6	c.1703C>G	p.Ala568Gly	missense	Exon 1 of 1	ENSP00000459565.1

Frequencies

GnomAD3 genomes

AF:

0.659

AC:

100097

AN:

151908

Hom.:

34079

Cov.:

show subpopulations

Gnomad AFR

AF:

0.834

Gnomad AMI

AF:

0.377

Gnomad AMR

AF:

0.679

Gnomad ASJ

AF:

0.630

Gnomad EAS

AF:

0.706

Gnomad SAS

AF:

0.642

Gnomad FIN

AF:

0.623

Gnomad MID

AF:

0.766

Gnomad NFE

AF:

0.555

Gnomad OTH

AF:

0.660

GnomAD2 exomes

AF:

0.628

AC:

156240

AN:

248734

AF XY:

0.624

show subpopulations

Gnomad AFR exome

AF:

0.837

Gnomad AMR exome

AF:

0.691

Gnomad ASJ exome

AF:

0.633

Gnomad EAS exome

AF:

0.702

Gnomad FIN exome

AF:

0.625

Gnomad NFE exome

AF:

0.560

Gnomad OTH exome

AF:

0.634

GnomAD4 exome

AF:

0.581

AC:

848761

AN:

1461428

Hom.:

249768

Cov.:

AF XY:

0.582

AC XY:

423312

AN XY:

726976

show subpopulations

African (AFR)

AF:

0.845

AC:

28298

AN:

33480

American (AMR)

AF:

0.690

AC:

30842

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.634

AC:

16574

AN:

26136

East Asian (EAS)

AF:

0.676

AC:

26846

AN:

39700

South Asian (SAS)

AF:

0.663

AC:

57230

AN:

86258

European-Finnish (FIN)

AF:

0.627

AC:

33346

AN:

53172

Middle Eastern (MID)

AF:

0.742

AC:

4281

AN:

5768

European-Non Finnish (NFE)

AF:

0.552

AC:

614238

AN:

1111822

Other (OTH)

AF:

0.615

AC:

37106

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

23724

47448

71173

94897

118621

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17450

34900

52350

69800

87250

<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:

0.659

AC:

100211

AN:

152026

Hom.:

34134

Cov.:

AF XY:

0.661

AC XY:

49104

AN XY:

74288

show subpopulations

African (AFR)

AF:

0.835

AC:

34624

AN:

41482

American (AMR)

AF:

0.680

AC:

10376

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.630

AC:

2186

AN:

3468

East Asian (EAS)

AF:

0.706

AC:

3650

AN:

5172

South Asian (SAS)

AF:

0.642

AC:

3090

AN:

4814

European-Finnish (FIN)

AF:

0.623

AC:

6573

AN:

10556

Middle Eastern (MID)

AF:

0.772

AC:

227

AN:

294

European-Non Finnish (NFE)

AF:

0.555

AC:

37740

AN:

67948

Other (OTH)

AF:

0.663

AC:

1401

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1672

3345

5017

6690

8362

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

786

1572

2358

3144

3930

<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:

0.589

Hom.:

8710

Bravo

AF:

0.673

TwinsUK

AF:

0.540

AC:

2003

ALSPAC

AF:

0.553

AC:

2132

ESP6500AA

AF:

0.832

AC:

3341

ESP6500EA

AF:

0.563

AC:

4705

ExAC

AF:

0.624

AC:

75429

Asia WGS

AF:

0.692

AC:

2403

AN:

3478

EpiCase

AF:

0.583

EpiControl

AF:

0.585

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Sep 16, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.29

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.22

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.66

MetaRNN

Benign

0.0000015

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.5

PhyloP100

9.8

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-3.4

REVEL

Uncertain

0.33

Sift

Uncertain

0.022

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.31

MPC

0.60

ClinPred

0.018

GERP RS

5.8

Varity_R

0.51

gMVP

0.38

Mutation Taster

=81/19

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over