chrX-14009128-C-T

Variant names:

• chrX-14009128-C-T
• rs145874697
• NM_001042479.2:c.514G>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.514G>A​(p.Val172Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000926 in 1,209,038 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 341 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00071 (0 hom., 24 hem., cov: 23)
  • Exomes 𝑓: 0.00095 (0 hom. 317 hem.)
• Consequence: GEMIN8 NM_001042479.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.97
• Publications: 3 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=0.015720248).
• BS2: High Hemizygotes in GnomAd4 at 24 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.514G>A	p.Val172Met	missense	Exon 5 of 5	NP_001035944.1	Q9NWZ8
	GEMIN8	NM_001042480.2		c.514G>A	p.Val172Met	missense	Exon 4 of 4	NP_001035945.1	Q9NWZ8
	GEMIN8	NM_017856.3		c.514G>A	p.Val172Met	missense	Exon 5 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.514G>A	p.Val172Met	missense	Exon 5 of 5	ENSP00000505429.1	Q9NWZ8
	GEMIN8	ENST00000398355.7	TSL:1	c.514G>A	p.Val172Met	missense	Exon 4 of 4	ENSP00000381398.3	Q9NWZ8
	GEMIN8	ENST00000380523.8	TSL:2	c.514G>A	p.Val172Met	missense	Exon 5 of 5	ENSP00000369895.4	Q9NWZ8

Frequencies

GnomAD3 genomes AF: 0.000710 AC: 80 AN: 112708 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000937

Gnomad ASJ AF: 0.00376

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00128

Gnomad OTH AF: 0.000658

GnomAD2 exomes AF: 0.000769 AC: 141 AN: 183241 AF XY: 0.000901

Gnomad AFR exome AF: 0.000152

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.00401

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000375

Gnomad NFE exome AF: 0.00122

Gnomad OTH exome AF: 0.000442

GnomAD4 exome AF: 0.000949 AC: 1040 AN: 1096330 Hom.: 0 Cov.: 30 AF XY: 0.000876 AC XY: 317 AN XY: 361730

African (AFR) AF: 0.0000379 AC: 1 AN: 26364

American (AMR) AF: 0.0000284 AC: 1 AN: 35201

Ashkenazi Jewish (ASJ) AF: 0.00356 AC: 69 AN: 19380

East Asian (EAS) AF: 0.00 AC: 0 AN: 30195

South Asian (SAS) AF: 0.00 AC: 0 AN: 54084

European-Finnish (FIN) AF: 0.000716 AC: 29 AN: 40526

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4128

European-Non Finnish (NFE) AF: 0.00106 AC: 895 AN: 840413

Other (OTH) AF: 0.000977 AC: 45 AN: 46039

GnomAD4 genome AF: 0.000710 AC: 80 AN: 112708 Hom.: 0 Cov.: 23 AF XY: 0.000689 AC XY: 24 AN XY: 34846

African (AFR) AF: 0.00 AC: 0 AN: 31062

American (AMR) AF: 0.0000937 AC: 1 AN: 10678

Ashkenazi Jewish (ASJ) AF: 0.00376 AC: 10 AN: 2658

East Asian (EAS) AF: 0.00 AC: 0 AN: 3586

South Asian (SAS) AF: 0.00 AC: 0 AN: 2735

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6229

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.00128 AC: 68 AN: 53312

Other (OTH) AF: 0.000658 AC: 1 AN: 1519

Alfa AF: 0.000875 Hom.: 11

Bravo AF: 0.000638

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000346 AC: 1

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.00119 AC: 8

ExAC AF: 0.000873 AC: 106

EpiCase AF: 0.000763

EpiControl AF: 0.00107

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.076	T
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.83	T
M_CAP	Pathogenic	0.46	D
MetaRNN	Benign	0.016	T
MetaSVM	Benign	-0.34	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		3.0
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.27
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.50
MVP		0.67
MPC		0.99
ClinPred		0.070	T
GERP RS		4.8
Varity_R		0.12
gMVP		0.61
Mutation Taster		=95/5	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: rs145874697; hg19: chrX-14027247;