Genetic Variant NM_015721.3:c.2974A>G (chr17-745069-T-C) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_015721.3(GEMIN4):c.2974A>G(p.Met992Val) variant causes a missense change. The variant allele was found at a frequency of 0.000559 in 1,613,690 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0031 ( 2 hom., cov: 33)

Exomes 𝑓: 0.00029 ( 2 hom. )

Consequence

GEMIN4
NM_015721.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 7.16

Publications

1 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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011332035).

BP6

Variant 17-745069-T-C is Benign according to our data. Variant chr17-745069-T-C is described in ClinVar as Benign. ClinVar VariationId is 734199.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GEMIN4	NM_015721.3	MANE Select	c.2974A>G	p.Met992Val	missense	Exon 2 of 2	NP_056536.2	P57678

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GEMIN4	ENST00000319004.6	TSL:1 MANE Select	c.2974A>G	p.Met992Val	missense	Exon 2 of 2	ENSP00000321706.5	P57678
	GEMIN4	ENST00000576778.1	TSL:6	c.2941A>G	p.Met981Val	missense	Exon 1 of 1	ENSP00000459565.1	I3L2C7

Frequencies

GnomAD3 genomes

AF:

0.00310

AC:

472

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0108

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000785

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00383

GnomAD2 exomes

AF:

0.000834

AC:

207

AN:

248348

AF XY:

0.000593

show subpopulations

Gnomad AFR exome

AF:

0.0111

Gnomad AMR exome

AF:

0.000784

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000267

Gnomad OTH exome

AF:

0.000663

GnomAD4 exome

AF:

0.000294

AC:

430

AN:

1461412

Hom.:

Cov.:

AF XY:

0.000239

AC XY:

174

AN XY:

726974

show subpopulations

African (AFR)

AF:

0.0103

AC:

344

AN:

33480

American (AMR)

AF:

0.000739

AC:

AN:

44682

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86230

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53258

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000989

AC:

AN:

1111800

Other (OTH)

AF:

0.000613

AC:

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

122

153

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.00310

AC:

472

AN:

152278

Hom.:

Cov.:

AF XY:

0.00283

AC XY:

211

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.0107

AC:

446

AN:

41562

American (AMR)

AF:

0.000784

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.000414

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68012

Other (OTH)

AF:

0.00379

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

117

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00111

Hom.:

Bravo

AF:

0.00336

ESP6500AA

AF:

0.00857

AC:

ESP6500EA

AF:

0.000119

AC:

ExAC

AF:

0.000802

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Uncertain

-0.060

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.23

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.77

MetaRNN

Benign

0.011

MetaSVM

Benign

-1.2

MutationAssessor

Uncertain

2.3

PhyloP100

7.2

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-3.1

REVEL

Uncertain

0.33

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.99

Vest4

0.77

MVP

0.67

MPC

0.60

ClinPred

0.031

GERP RS

5.8

Varity_R

0.72

gMVP

0.61

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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

Computational scores

Splicing

Publications

Other links and lift over