X-14009128-C-T

Variant names:

• chrX-14009128-C-T
• rs145874697
• NM_001042479.2:c.514G>A

Variant summary

Our verdict is Benign. Variant got -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

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

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015720248).
• BS2: High Hemizygotes in GnomAd4 at 24 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GEMIN8	NM_001042479.2	c.514G>A	p.Val172Met	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.514G>A	p.Val172Met	missense_variant	Exon 5 of 5		NM_001042479.2	ENSP00000505429.1

Frequencies

GnomAD3 genomes AF: 0.000710 AC: 80 AN: 112708 Hom.: 0 Cov.: 23 AF XY: 0.000689 AC XY: 24 AN XY: 34846

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

GnomAD3 exomes AF: 0.000769 AC: 141 AN: 183241 Hom.: 0 AF XY: 0.000901 AC XY: 61 AN XY: 67723

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 SAS 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

Gnomad4 AFR exome AF: 0.0000379

Gnomad4 AMR exome AF: 0.0000284

Gnomad4 ASJ exome AF: 0.00356

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000716

Gnomad4 NFE exome AF: 0.00106

Gnomad4 OTH exome AF: 0.000977

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

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000937

Gnomad4 ASJ AF: 0.00376

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00128

Gnomad4 OTH AF: 0.000658

Alfa AF: 0.000987 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

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 06, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.514G>A (p.V172M) 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 514, causing the valine (V) at amino acid position 172 to be replaced by a methionine (M). 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	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;T;T
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.83	.;T;T
M_CAP	Pathogenic	0.46	D
MetaRNN	Benign	0.016	T;T;T
MetaSVM	Benign	-0.34	T
MutationAssessor	Uncertain	2.3	M;M;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-2.1	N;N;N
REVEL	Benign	0.27
Sift	Uncertain	0.0040	D;D;D
Sift4G	Uncertain	0.0040	D;D;D
Polyphen		1.0	D;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs145874697; hg19: chrX-14027247;