chrX-14009034-C-T

Variant names:

• chrX-14009034-C-T
• rs768846924
• NM_001042479.2:c.608G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001042479.2(GEMIN8):​c.608G>A​(p.Arg203His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000107 in 1,210,590 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R203L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.000010 (0 hom. 4 hem.)
• Consequence: GEMIN8 NM_001042479.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.553
• Publications: 1 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03326738).
• BS2: High Hemizygotes in GnomAdExome4 at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GEMIN8	NM_001042479.2	c.608G>A	p.Arg203His	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.608G>A	p.Arg203His	missense_variant	Exon 5 of 5		NM_001042479.2	ENSP00000505429.1

Frequencies

GnomAD3 genomes AF: 0.0000178 AC: 2 AN: 112452 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000561

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000218 AC: 4 AN: 183466 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000144

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000244

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000100 AC: 11 AN: 1098086 Hom.: 0 Cov.: 30 AF XY: 0.0000110 AC XY: 4 AN XY: 363440

African (AFR) AF: 0.00 AC: 0 AN: 26401

American (AMR) AF: 0.00 AC: 0 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19384

East Asian (EAS) AF: 0.00 AC: 0 AN: 30205

South Asian (SAS) AF: 0.0000739 AC: 4 AN: 54149

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40532

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4130

European-Non Finnish (NFE) AF: 0.00000713 AC: 6 AN: 841986

Other (OTH) AF: 0.0000217 AC: 1 AN: 46092

GnomAD4 genome AF: 0.0000178 AC: 2 AN: 112504 Hom.: 0 Cov.: 23 AF XY: 0.0000289 AC XY: 1 AN XY: 34642

African (AFR) AF: 0.00 AC: 0 AN: 31024

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2650

East Asian (EAS) AF: 0.000562 AC: 2 AN: 3557

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6187

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53234

Other (OTH) AF: 0.00 AC: 0 AN: 1539

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 01, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.608G>A (p.R203H) 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 608, causing the arginine (R) at amino acid position 203 to be replaced by a histidine (H). 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	0.095
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.91
CADD	Benign	12
DANN	Uncertain	0.98
DEOGEN2	Benign	0.11	T;T
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.73	.;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.033	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;L
PhyloP100		0.55
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.9	N;N
REVEL	Benign	0.085
Sift	Benign	0.094	T;T
Sift4G	Benign	0.061	T;T
Polyphen		0.12	B;B
Vest4		0.050
MutPred		0.26		Loss of MoRF binding (P = 0.0086);Loss of MoRF binding (P = 0.0086);
MVP		0.39
MPC		0.45
ClinPred		0.033	T
GERP RS		-3.9
Varity_R		0.049
gMVP		0.57
Mutation Taster		=97/3	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: rs768846924; hg19: chrX-14027153; COSMIC: COSV60551446; COSMIC: COSV60551446;