Genetic Variant NM_001042479.2:c.586C>T (chrX-14009056-G-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001042479.2(GEMIN8):c.586C>T(p.Arg196Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000273 in 1,097,639 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0000027 ( 0 hom. 2 hem. )

Consequence

GEMIN8
NM_001042479.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.29

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.

BS2

High Hemizygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GEMIN8	NM_001042479.2 link	c.586C>T	p.Arg196Trp	missense_variant	Exon 5 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.586C>T	p.Arg196Trp	missense_variant	Exon 5 of 5		NM_001042479.2	ENSP00000505429.1		Q9NWZ8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000545

AC:

AN:

183443

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000122

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000273

AC:

AN:

1097639

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

363003

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26389

American (AMR)

AF:

0.00

AC:

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19381

East Asian (EAS)

AF:

0.00

AC:

AN:

30203

South Asian (SAS)

AF:

0.00

AC:

AN:

54137

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40522

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4131

European-Non Finnish (NFE)

AF:

0.00000356

AC:

AN:

841589

Other (OTH)

AF:

0.00

AC:

AN:

46080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 19, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.586C>T (p.R196W) alteration is located in exon 5 (coding exon 3) of the GEMIN8 gene. This alteration results from a C to T substitution at nucleotide position 586, causing the arginine (R) at amino acid position 196 to be replaced by a tryptophan (W). 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

0.28

BayesDel_addAF

Uncertain

0.040

BayesDel_noAF

Benign

-0.18

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.074

T;T

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.84

.;T

M_CAP

Uncertain

0.096

MetaRNN

Uncertain

0.61

D;D

MetaSVM

Benign

-0.72

MutationAssessor

Benign

1.9

L;L

PhyloP100

3.3

PrimateAI

Uncertain

0.51

PROVEAN

Pathogenic

-5.8

D;D

REVEL

Uncertain

0.39

Sift

Uncertain

0.0010

D;D

Sift4G

Benign

0.085

T;T

Polyphen

1.0

D;D

Vest4

0.72

MutPred

0.40

Loss of disorder (P = 0.0094);Loss of disorder (P = 0.0094);

MVP

0.64

MPC

0.43

ClinPred

0.99

GERP RS

3.4

Varity_R

0.69

gMVP

0.90

Mutation Taster

=55/45

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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NM_001042479.2:c.586C>T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over