rs61749643

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 1P and 6B. PP5BP4BS1_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).

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

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 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

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 id is 562188.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=2}.

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 FAILED 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GEMIN5	NM_015465.5 link	c.3046C>T	p.Arg1016Cys	missense_variant	Exon 22 of 28	ENST00000285873.8	NP_056280.2
GEMIN5	NM_001252156.2 link	c.3043C>T	p.Arg1015Cys	missense_variant	Exon 22 of 28		NP_001239085.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GEMIN5	ENST00000285873.8 link	c.3046C>T	p.Arg1016Cys	missense_variant	Exon 22 of 28	1	NM_015465.5	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

Gnomad4 AFR exome

AF:

0.00153

AC:

AN:

33418

Gnomad4 AMR exome

AF:

0.00457

AC:

203

AN:

44442

Gnomad4 ASJ exome

AF:

0.00211

AC:

AN:

26082

Gnomad4 EAS exome

AF:

0.0000253

AC:

AN:

39604

Gnomad4 SAS exome

AF:

0.00199

AC:

170

AN:

85548

Gnomad4 FIN exome

AF:

0.000524

AC:

AN:

53400

Gnomad4 NFE exome

AF:

0.00878

AC:

9750

AN:

1110792

Gnomad4 Remaining exome

AF:

0.00610

AC:

368

AN:

60300

Heterozygous variant carriers

506

1011

1517

2022

2528

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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

Gnomad4 AFR

AF:

0.00207

AC:

0.0020695

AN:

0.0020695

Gnomad4 AMR

AF:

0.00555

AC:

0.00555483

AN:

0.00555483

Gnomad4 ASJ

AF:

0.00173

AC:

0.00172811

AN:

0.00172811

Gnomad4 EAS

AF:

0.000193

AC:

0.00019305

AN:

0.00019305

Gnomad4 SAS

AF:

0.00207

AC:

0.00207125

AN:

0.00207125

Gnomad4 FIN

AF:

0.0000942

AC:

0.0000941797

AN:

0.0000941797

Gnomad4 NFE

AF:

0.00722

AC:

0.00721825

AN:

0.00721825

Gnomad4 OTH

AF:

0.00568

AC:

0.00567644

AN:

0.00567644

Heterozygous variant carriers

121

151

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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

TwinsUK

AF:

0.00620

AC:

ALSPAC

AF:

0.00960

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00860

AC:

ExAC

AF:

0.00453

AC:

550

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00635

EpiControl

AF:

0.00764

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Uncertain:1

Apr 12, 2024

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrated reduced dimerization and ribosome association compared to wildtype (PMID: 35393353); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 35295849, 35393353, 36980979, 16677673, 38316953) -

Mar 08, 2018

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

GEMIN5: PM3:Strong, PM1, PM2:Supporting, PS3:Supporting, BP4 -

not specified

Uncertain:1

May 09, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: GEMIN5 c.3046C>T (p.Arg1016Cys) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 0.0046 in 249516 control chromosomes in the gnomAD database, including 5 homozygotes. The observed variant frequency exceeds the estimated maximal expected allele frequency for a pathogenic variant in GEMIN5 causing GEMIN5-Related Disorder phenotype. c.3046C>T has been observed in multiple compound heterozygous individuals affected with GEMIN5-Related Disorder (Rajan_2022, Francisco-Velilla_2022, Cascajo-Almenara_2024). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 30%-<50% of normal activity (Francisco-Velilla_2022). ClinVar contains an entry for this variant (Variation ID: 562188). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.21

CADD

Pathogenic

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

PrimateAI

Benign

0.38

PROVEAN

Uncertain

-2.7

REVEL

Uncertain

0.40

Sift

Uncertain

0.013

Sift4G

Uncertain

0.015

Polyphen

1.0

Vest4

0.60

MVP

0.79

MPC

0.45

ClinPred

0.024

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.35

gMVP

0.40

Mutation Taster

=87/13

polymorphism

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over