Genetic Variant GEMIN8:p.Ser117Cys (chrX-14020200-G-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM1BP4_ModerateBS2

The NM_001042479.2(GEMIN8):c.350C>G(p.Ser117Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000813 in 1,205,897 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 29 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000036 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.000086 ( 0 hom. 28 hem. )

Consequence

GEMIN8
NM_001042479.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.409

Publications

0 publications found

Variant links:

Genes affected

GEMIN8 (HGNC:26044): (gem nuclear organelle associated protein 8) The protein encoded by this gene is part of the SMN complex, which is necessary for spliceosomal snRNP assembly in the cytoplasm and pre-mRNA splicing in the nucleus. The encoded protein binds to both SMN1 and the GEMIN6/GEMIN7 heterodimer, mediating their interaction. This protein is found in nuclear Gemini of Cajal bodies (gems) and in the cytoplasm. Three transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, May 2010]

GEMIN8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PM1

In a modified_residue Phosphoserine (size 0) in uniprot entity GEMI8_HUMAN

BP4

Computational evidence support a benign effect (MetaRNN=0.07242721).

BS2

High Hemizygotes in GnomAdExome4 at 28 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GEMIN8	NM_001042479.2 link	c.350C>G	p.Ser117Cys	missense_variant	Exon 4 of 5	ENST00000680255.1	NP_001035944.1	Q9NWZ8A0A024RBX2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GEMIN8	ENST00000680255.1 link	c.350C>G	p.Ser117Cys	missense_variant	Exon 4 of 5		NM_001042479.2	ENSP00000505429.1		Q9NWZ8

Frequencies

GnomAD3 genomes

AF:

0.0000359

AC:

AN:

111301

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000754

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000600

AC:

AN:

183367

AF XY:

0.0000737

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000365

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000122

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000859

AC:

AN:

1094596

Hom.:

Cov.:

AF XY:

0.0000778

AC XY:

AN XY:

360058

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26334

American (AMR)

AF:

0.0000284

AC:

AN:

35206

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19365

East Asian (EAS)

AF:

0.0000331

AC:

AN:

30194

South Asian (SAS)

AF:

0.0000185

AC:

AN:

54052

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40527

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4121

European-Non Finnish (NFE)

AF:

0.000101

AC:

AN:

838815

Other (OTH)

AF:

0.000130

AC:

AN:

45982

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000359

AC:

AN:

111301

Hom.:

Cov.:

AF XY:

0.0000298

AC XY:

AN XY:

33505

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30556

American (AMR)

AF:

0.00

AC:

AN:

10454

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2638

East Asian (EAS)

AF:

0.00

AC:

AN:

3556

South Asian (SAS)

AF:

0.00

AC:

AN:

2637

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5979

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.0000754

AC:

AN:

53060

Other (OTH)

AF:

0.00

AC:

AN:

1502

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000491

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000346

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.0000576

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 18, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.350C>G (p.S117C) alteration is located in exon 4 (coding exon 2) of the GEMIN8 gene. This alteration results from a C to G substitution at nucleotide position 350, causing the serine (S) at amino acid position 117 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.83

CADD

Benign

2.8

(source)

DANN

Benign

0.49

DEOGEN2

Benign

0.0078

T;T;T

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.27

.;T;T

M_CAP

Benign

0.079

MetaRNN

Benign

0.072

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.2

L;L;.

PhyloP100

0.41

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.75

N;N;N

REVEL

Benign

0.047

Sift

Benign

0.096

T;T;T

Sift4G

Benign

0.16

T;T;T

Polyphen

0.0020

B;B;.

Vest4

0.089

MVP

0.15

MPC

0.34

ClinPred

0.038

GERP RS

-0.54

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.095

gMVP

0.15

Mutation Taster

=99/1

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

Publications

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X-14020200-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over