NM_001042479.2:c.686G>A

Variant names:

• chrX-14008956-C-T
• rs202083813
• NM_001042479.2:c.686G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001042479.2(GEMIN8):​c.686G>A​(p.Arg229Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,209,215 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.0000064 (0 hom. 1 hem.)
• Consequence: GEMIN8 NM_001042479.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.660
• Publications: 2 publications found

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]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15985918).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GEMIN8	NM_001042479.2	c.686G>A	p.Arg229Gln	missense_variant	Exon 5 of 5	ENST00000680255.1	NP_001035944.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GEMIN8	ENST00000680255.1	c.686G>A	p.Arg229Gln	missense_variant	Exon 5 of 5		NM_001042479.2	ENSP00000505429.1

Frequencies

GnomAD3 genomes AF: 0.0000178 AC: 2 AN: 112481 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000323

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: 0.0000188

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000164 AC: 3 AN: 183252 AF XY: 0.0000295

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: 0.0000367

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000638 AC: 7 AN: 1096681 Hom.: 0 Cov.: 29 AF XY: 0.00000276 AC XY: 1 AN XY: 362073

African (AFR) AF: 0.0000758 AC: 2 AN: 26373

American (AMR) AF: 0.00 AC: 0 AN: 35204

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19371

East Asian (EAS) AF: 0.00 AC: 0 AN: 30202

South Asian (SAS) AF: 0.00 AC: 0 AN: 54098

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40530

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4121

European-Non Finnish (NFE) AF: 0.00000476 AC: 4 AN: 840739

Other (OTH) AF: 0.0000217 AC: 1 AN: 46043

GnomAD4 genome AF: 0.0000178 AC: 2 AN: 112534 Hom.: 0 Cov.: 23 AF XY: 0.0000288 AC XY: 1 AN XY: 34694

African (AFR) AF: 0.0000323 AC: 1 AN: 31006

American (AMR) AF: 0.00 AC: 0 AN: 10694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2647

East Asian (EAS) AF: 0.00 AC: 0 AN: 3561

South Asian (SAS) AF: 0.00 AC: 0 AN: 2713

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6213

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53264

Other (OTH) AF: 0.00 AC: 0 AN: 1534

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 29, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.686G>A (p.R229Q) alteration is located in exon 5 (coding exon 3) of the GEMIN8 gene. This alteration results from a G to A substitution at nucleotide position 686, causing the arginine (R) at amino acid position 229 to be replaced by a glutamine (Q). 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	0.089
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0067	T;T
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.76	.;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M;M
PhyloP100		0.66
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.95	N;N
REVEL	Benign	0.072
Sift	Benign	0.22	T;T
Sift4G	Benign	0.18	T;T
Polyphen		1.0	D;D
Vest4		0.13
MutPred		0.33		Gain of ubiquitination at K233 (P = 0.0467);Gain of ubiquitination at K233 (P = 0.0467);
MVP		0.55
MPC		1.1
ClinPred		0.56	D
GERP RS		1.9
Varity_R		0.091
gMVP		0.77
Mutation Taster		=100/0	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

Other links and lift over

dbSNP: rs202083813; hg19: chrX-14027075;