X-14020351-C-A

Variant names:

• chrX-14020351-C-A
• rs371906124
• NM_001042479.2:c.199G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001042479.2(GEMIN8):​c.199G>T​(p.Asp67Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,109 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D67N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
• Consequence: GEMIN8 NM_001042479.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.122
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.076527745).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001042479.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GEMIN8	NM_001042479.2	MANE Select	c.199G>T	p.Asp67Tyr	missense	Exon 4 of 5	NP_001035944.1	Q9NWZ8
	GEMIN8	NM_001042480.2		c.199G>T	p.Asp67Tyr	missense	Exon 3 of 4	NP_001035945.1	Q9NWZ8
	GEMIN8	NM_017856.3		c.199G>T	p.Asp67Tyr	missense	Exon 4 of 5	NP_060326.1	Q9NWZ8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GEMIN8	ENST00000680255.1	MANE Select	c.199G>T	p.Asp67Tyr	missense	Exon 4 of 5	ENSP00000505429.1	Q9NWZ8
	GEMIN8	ENST00000398355.7	TSL:1	c.199G>T	p.Asp67Tyr	missense	Exon 3 of 4	ENSP00000381398.3	Q9NWZ8
	GEMIN8	ENST00000380523.8	TSL:2	c.199G>T	p.Asp67Tyr	missense	Exon 4 of 5	ENSP00000369895.4	Q9NWZ8

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097109 Hom.: 0 Cov.: 29 AF XY: 0.00000276 AC XY: 1 AN XY: 362477

African (AFR) AF: 0.0000379 AC: 1 AN: 26373

American (AMR) AF: 0.00 AC: 0 AN: 35206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19378

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 54118

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40525

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4129

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841123

Other (OTH) AF: 0.00 AC: 0 AN: 46055

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.7
DANN	Benign	0.97
DEOGEN2	Benign	0.012	T
FATHMM_MKL	Benign	0.091	N
LIST_S2	Benign	0.40	T
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.077	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		-0.12
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.095
Sift	Benign	0.038	D
Sift4G	Uncertain	0.031	D
Polyphen		0.96	D
Vest4		0.18
MutPred		0.21		Loss of solvent accessibility (P = 0.0509)
MVP		0.082
MPC		0.96
ClinPred		0.27	T
GERP RS		2.0
Varity_R		0.044
gMVP		0.35
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs371906124; hg19: chrX-14038470; COSMIC: COSV107411704;