rs61749643

Positions:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The ENST00000285873.8(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
ENST00000285873.8 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2B:1

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01176995).

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. 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/exons	MANE	Protein	UniProt
GEMIN5	NM_015465.5 linkuse as main transcript	c.3046C>T	p.Arg1016Cys	missense_variant	22/28	ENST00000285873.8	NP_056280.2
GEMIN5	NM_001252156.2 linkuse as main transcript	c.3043C>T	p.Arg1015Cys	missense_variant	22/28		NP_001239085.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GEMIN5	ENST00000285873.8 linkuse as main transcript	c.3046C>T	p.Arg1016Cys	missense_variant	22/28	1	NM_015465.5	ENSP00000285873	P1

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

GnomAD3 exomes

AF:

0.00460

AC:

1149

AN:

249516

Hom.:

AF XY:

0.00463

AC XY:

624

AN XY:

134888

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 SAS exome

AF:

0.00211

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

Gnomad4 AMR exome

AF:

0.00457

Gnomad4 ASJ exome

AF:

0.00211

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.00199

Gnomad4 FIN exome

AF:

0.000524

Gnomad4 NFE exome

AF:

0.00878

Gnomad4 OTH exome

AF:

0.00610

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

Gnomad4 AMR

AF:

0.00555

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00207

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.00722

Gnomad4 OTH

AF:

0.00568

Alfa

AF:

0.00616

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:1Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:2Benign:1

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 12, 2024	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) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	GEMIN5: BP4, BS2 -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 08, 2018	- -

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

MutationTaster

Benign

1.0

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

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