X-14020281-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001042479.2(GEMIN8):​c.269C>G​(p.Ser90Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000912 in 1,096,854 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 23)
Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )

Consequence

GEMIN8
NM_001042479.2 missense

Scores

1
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.506
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.10461968).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GEMIN8NM_001042479.2 linkc.269C>G p.Ser90Cys 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
GEMIN8ENST00000680255.1 linkc.269C>G p.Ser90Cys missense_variant Exon 4 of 5 NM_001042479.2 ENSP00000505429.1 Q9NWZ8

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD4 exome
AF:
9.12e-7
AC:
1
AN:
1096854
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
362214
show subpopulations
Gnomad4 AFR exome
AF:
0.0000379
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
23
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Feb 20, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.269C>G (p.S90C) 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 269, causing the serine (S) at amino acid position 90 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
0.087
BayesDel_addAF
Benign
-0.39
T
BayesDel_noAF
Benign
-0.80
CADD
Benign
4.4
DANN
Benign
0.95
DEOGEN2
Benign
0.013
T;T;T
FATHMM_MKL
Benign
0.14
N
LIST_S2
Benign
0.44
.;T;T
M_CAP
Uncertain
0.15
D
MetaRNN
Benign
0.10
T;T;T
MetaSVM
Benign
-0.96
T
MutationAssessor
Benign
1.4
L;L;.
PrimateAI
Benign
0.27
T
PROVEAN
Benign
-1.6
N;N;N
REVEL
Benign
0.026
Sift
Benign
0.18
T;T;T
Sift4G
Benign
0.18
T;T;T
Polyphen
0.99
D;D;.
Vest4
0.15
MutPred
0.26
Loss of disorder (P = 0.0276);Loss of disorder (P = 0.0276);Loss of disorder (P = 0.0276);
MVP
0.33
MPC
0.34
ClinPred
0.25
T
GERP RS
-1.5
Varity_R
0.099
gMVP
0.10

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.

Other links and lift over

dbSNP: rs1924217058; hg19: chrX-14038400; API