X-14020459-C-A

Variant names:

• chrX-14020459-C-A
• rs61740319
• NM_001042479.2:c.91G>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001042479.2(GEMIN8):​c.91G>T​(p.Ala31Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00812 in 1,205,727 control chromosomes in the GnomAD database, including 41 homozygotes. There are 3,075 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0061 (2 hom., 200 hem., cov: 23)
  • Exomes 𝑓: 0.0083 (39 hom. 2875 hem.)
• Consequence: GEMIN8 NM_001042479.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.98
• Publications: 5 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008584619).
• BP6: Variant X-14020459-C-A is Benign according to our data. Variant chrX-14020459-C-A is described in ClinVar as Benign. ClinVar VariationId is 719272.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 2 gene

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.91G>T	p.Ala31Ser	missense	Exon 4 of 5	NP_001035944.1	Q9NWZ8
	GEMIN8	NM_001042480.2		c.91G>T	p.Ala31Ser	missense	Exon 3 of 4	NP_001035945.1	Q9NWZ8
	GEMIN8	NM_017856.3		c.91G>T	p.Ala31Ser	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.91G>T	p.Ala31Ser	missense	Exon 4 of 5	ENSP00000505429.1	Q9NWZ8
	GEMIN8	ENST00000398355.7	TSL:1	c.91G>T	p.Ala31Ser	missense	Exon 3 of 4	ENSP00000381398.3	Q9NWZ8
	GEMIN8	ENST00000380523.8	TSL:2	c.91G>T	p.Ala31Ser	missense	Exon 4 of 5	ENSP00000369895.4	Q9NWZ8

Frequencies

GnomAD3 genomes AF: 0.00609 AC: 682 AN: 112024 Hom.: 2 Cov.: 23

Gnomad AFR AF: 0.00107

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00160

Gnomad ASJ AF: 0.00642

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000747

Gnomad FIN AF: 0.00998

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0103

Gnomad OTH AF: 0.00332

GnomAD2 exomes AF: 0.00597 AC: 1094 AN: 183402 AF XY: 0.00603

Gnomad AFR exome AF: 0.000760

Gnomad AMR exome AF: 0.00106

Gnomad ASJ exome AF: 0.0110

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00743

Gnomad NFE exome AF: 0.0100

Gnomad OTH exome AF: 0.00486

GnomAD4 exome AF: 0.00832 AC: 9104 AN: 1093653 Hom.: 39 Cov.: 28 AF XY: 0.00800 AC XY: 2875 AN XY: 359173

African (AFR) AF: 0.00110 AC: 29 AN: 26315

American (AMR) AF: 0.00134 AC: 47 AN: 35205

Ashkenazi Jewish (ASJ) AF: 0.00945 AC: 183 AN: 19355

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30196

South Asian (SAS) AF: 0.000611 AC: 33 AN: 54039

European-Finnish (FIN) AF: 0.00738 AC: 299 AN: 40526

Middle Eastern (MID) AF: 0.00534 AC: 22 AN: 4122

European-Non Finnish (NFE) AF: 0.00972 AC: 8144 AN: 837968

Other (OTH) AF: 0.00753 AC: 346 AN: 45927

GnomAD4 genome AF: 0.00609 AC: 682 AN: 112074 Hom.: 2 Cov.: 23 AF XY: 0.00584 AC XY: 200 AN XY: 34244

African (AFR) AF: 0.00107 AC: 33 AN: 30867

American (AMR) AF: 0.00160 AC: 17 AN: 10608

Ashkenazi Jewish (ASJ) AF: 0.00642 AC: 17 AN: 2650

East Asian (EAS) AF: 0.00 AC: 0 AN: 3575

South Asian (SAS) AF: 0.000750 AC: 2 AN: 2668

European-Finnish (FIN) AF: 0.00998 AC: 61 AN: 6115

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

European-Non Finnish (NFE) AF: 0.0103 AC: 547 AN: 53167

Other (OTH) AF: 0.00328 AC: 5 AN: 1524

Alfa AF: 0.00543 Hom.: 39

Bravo AF: 0.00509

TwinsUK AF: 0.00809 AC: 30

ALSPAC AF: 0.0118 AC: 34

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.0109 AC: 73

ExAC AF: 0.00625 AC: 759

EpiCase AF: 0.0104

EpiControl AF: 0.00877

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.025	T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0086	T
MetaSVM	Benign	-0.48	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		5.0
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.23
Sift	Uncertain	0.018	D
Sift4G	Benign	0.081	T
Polyphen		1.0	D
Vest4		0.21
MVP		0.38
MPC		0.95
ClinPred		0.016	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.41
gMVP		0.46
Mutation Taster		=96/4	polymorphism (auto)

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: rs61740319; hg19: chrX-14038578; COSMIC: COSV60551575;