rs61749643

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 5P and 6B. PS3PP5BP4BS1_SupportingBS2

The NM_015465.5(GEMIN5):c.3046C>T(p.Arg1016Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00704 in 1,611,648 control chromosomes in the GnomAD database, including 58 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV005379955: Published functional studies demonstrated reduced dimerization and ribosome association compared to wildtype (PMID:35393353);".

Frequency

Genomes: 𝑓 0.0045 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0073 ( 56 hom. )

Consequence

GEMIN5
NM_015465.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:2

Conservation

PhyloP100: 6.14

Publications

13 publications found

Variant links:

Genes affected

GEMIN5 (HGNC:20043): (gem nuclear organelle associated protein 5) This gene encodes a WD repeat protein that is a component of the survival of motor neurons (SMN) complex. The SMN complex plays a critical role in mRNA splicing through the assembly of spliceosomal small nuclear ribonucleoproteins (snRNPs), and may also mediate the assembly and transport of other classes of ribonucleoproteins. The encoded protein is the snRNA-binding component of the SMN complex. Dysregulation of this gene may play a role in alternative mRNA splicing and tumor cell motility. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Nov 2011]

GEMIN5 Gene-Disease associations (from GenCC):

neurodevelopmental disorder with cerebellar atrophy and motor dysfunction
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae)

GEMIN5 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_015465.5, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV005379955: Published functional studies demonstrated reduced dimerization and ribosome association compared to wildtype (PMID: 35393353);

PP5

Variant 5-154899279-G-A is Pathogenic according to our data. Variant chr5-154899279-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 562188.

BP4

Computational evidence support a benign effect (MetaRNN=0.01176995). . Strength limited to SUPPORTING due to the PP5.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00454 (692/152298) while in subpopulation NFE AF = 0.00722 (491/68022). AF 95% confidence interval is 0.00669. There are 2 homozygotes in GnomAd4. There are 314 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015465.5. 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
	GEMIN5	NM_015465.5	MANE Select	c.3046C>T	p.Arg1016Cys	missense	Exon 22 of 28	NP_056280.2	Q8TEQ6
	GEMIN5	NM_001252156.2		c.3043C>T	p.Arg1015Cys	missense	Exon 22 of 28	NP_001239085.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GEMIN5	ENST00000285873.8	TSL:1 MANE Select	c.3046C>T	p.Arg1016Cys	missense	Exon 22 of 28	ENSP00000285873.6	Q8TEQ6

Frequencies

GnomAD3 genomes

AF:

0.00454

AC:

691

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00208

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00556

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00722

Gnomad OTH

AF:

0.00574

GnomAD2 exomes

AF:

0.00460

AC:

1149

AN:

249516

AF XY:

0.00463

show subpopulations

Gnomad AFR exome

AF:

0.00216

Gnomad AMR exome

AF:

0.00433

Gnomad ASJ exome

AF:

0.00280

Gnomad EAS exome

AF:

0.0000548

Gnomad FIN exome

AF:

0.000324

Gnomad NFE exome

AF:

0.00737

Gnomad OTH exome

AF:

0.00542

GnomAD4 exome

AF:

0.00730

AC:

10654

AN:

1459350

Hom.:

Cov.:

AF XY:

0.00709

AC XY:

5144

AN XY:

725854

show subpopulations

African (AFR)

AF:

0.00153

AC:

AN:

33418

American (AMR)

AF:

0.00457

AC:

203

AN:

44442

Ashkenazi Jewish (ASJ)

AF:

0.00211

AC:

AN:

26082

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39604

South Asian (SAS)

AF:

0.00199

AC:

170

AN:

85548

European-Finnish (FIN)

AF:

0.000524

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.00486

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00878

AC:

9750

AN:

1110792

Other (OTH)

AF:

0.00610

AC:

368

AN:

60300

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

506

1011

1517

2022

2528

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

402

804

1206

1608

2010

<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:

0.00454

AC:

692

AN:

152298

Hom.:

Cov.:

AF XY:

0.00422

AC XY:

314

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.00207

AC:

AN:

41556

American (AMR)

AF:

0.00555

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5180

South Asian (SAS)

AF:

0.00207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00722

AC:

491

AN:

68022

Other (OTH)

AF:

0.00568

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

121

151

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.00600

Hom.:

Bravo

AF:

0.00505

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00635

EpiControl

AF:

0.00764

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.21

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.15

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.012

MetaSVM

Benign

-0.36

MutationAssessor

Benign

1.1

PhyloP100

6.1

PrimateAI

Benign

0.38

PROVEAN

Uncertain

-2.7

REVEL

Uncertain

0.40

Sift

Uncertain

0.013

Sift4G

Uncertain

0.015

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.35

gMVP

0.40

Mutation Taster

=87/13

polymorphism

(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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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

Computational scores

Splicing

Publications

Other links and lift over