rs4968104

chr17-746265-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015721.3(GEMIN4):c.1778A>T(p.Glu593Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.235 in 1,613,572 control chromosomes in the GnomAD database, including 46,738 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3260 hom., cov: 32)
  • Exomes 𝑓: 0.24 (43478 hom.)
• Consequence: GEMIN4 NM_015721.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0140

Genes affected

GEMIN4 (HGNC:15717): (gem nuclear organelle associated protein 4) The product of this gene is part of a large complex localized to the cytoplasm, nucleoli, and to discrete nuclear bodies called Gemini bodies (gems). The complex functions in spliceosomal snRNP assembly in the cytoplasm, and regenerates spliceosomes required for pre-mRNA splicing in the nucleus. The encoded protein directly interacts with a DEAD box protein and several spliceosome core proteins. Alternatively spliced transcript variants have been described, but their biological validity has not been determined. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0046203732).
• BP6: Variant 17-746265-T-A is Benign according to our data. Variant chr17-746265-T-A is described in ClinVar as [Benign]. Clinvar id is 1222413.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.253 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GEMIN4	NM_015721.3	c.1778A>T	p.Glu593Val	missense_variant	2/2	ENST00000319004.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GEMIN4	ENST00000319004.6	c.1778A>T	p.Glu593Val	missense_variant	2/2	1	NM_015721.3	P1
GEMIN4	ENST00000576778.1	c.1745A>T	p.Glu582Val	missense_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.191 AC: 28999 AN: 152004 Hom.: 3258 Cov.: 32

Gnomad AFR AF: 0.0908

Gnomad AMI AF: 0.408

Gnomad AMR AF: 0.159

Gnomad ASJ AF: 0.244

Gnomad EAS AF: 0.124

Gnomad SAS AF: 0.219

Gnomad FIN AF: 0.188

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.256

Gnomad OTH AF: 0.210

GnomAD3 exomes AF: 0.204 AC: 50811 AN: 249018 Hom.: 5725 AF XY: 0.209 AC XY: 28211 AN XY: 135164

Gnomad AFR exome AF: 0.0907

Gnomad AMR exome AF: 0.119

Gnomad ASJ exome AF: 0.246

Gnomad EAS exome AF: 0.114

Gnomad SAS exome AF: 0.200

Gnomad FIN exome AF: 0.193

Gnomad NFE exome AF: 0.259

Gnomad OTH exome AF: 0.215

GnomAD4 exome AF: 0.239 AC: 349816 AN: 1461450 Hom.: 43478 Cov.: 68 AF XY: 0.238 AC XY: 173337 AN XY: 726970

Gnomad4 AFR exome AF: 0.0855

Gnomad4 AMR exome AF: 0.125

Gnomad4 ASJ exome AF: 0.243

Gnomad4 EAS exome AF: 0.145

Gnomad4 SAS exome AF: 0.194

Gnomad4 FIN exome AF: 0.191

Gnomad4 NFE exome AF: 0.259

Gnomad4 OTH exome AF: 0.232

GnomAD4 genome AF: 0.191 AC: 29005 AN: 152122 Hom.: 3260 Cov.: 32 AF XY: 0.189 AC XY: 14036 AN XY: 74362

Gnomad4 AFR AF: 0.0907

Gnomad4 AMR AF: 0.159

Gnomad4 ASJ AF: 0.244

Gnomad4 EAS AF: 0.124

Gnomad4 SAS AF: 0.219

Gnomad4 FIN AF: 0.188

Gnomad4 NFE AF: 0.257

Gnomad4 OTH AF: 0.208

Alfa AF: 0.244 Hom.: 3531

Bravo AF: 0.184

TwinsUK AF: 0.265 AC: 984

ALSPAC AF: 0.263 AC: 1012

ESP6500AA AF: 0.0918 AC: 361

ESP6500EA AF: 0.252 AC: 2103

ExAC AF: 0.208 AC: 25111

Asia WGS AF: 0.189 AC: 660 AN: 3478

EpiCase AF: 0.248

EpiControl AF: 0.251

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

GEMIN4-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 17, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 28, 2020

This variant is associated with the following publications: (PMID: 22639842) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	9.2
Dann	Benign	0.90
DEOGEN2	Benign	0.028	T;.
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.51	T;T
MetaRNN	Benign	0.0046	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.2	M;.
MutationTaster	Benign	0.94	P;P
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.7	N;.
REVEL	Benign	0.14
Sift	Benign	0.14	T;.
Sift4G	Benign	0.14	T;T
Polyphen		0.28	B;.
Vest4		0.16
MPC		0.24
ClinPred		0.018	T
GERP RS		5.5
Varity_R		0.054
gMVP		0.30

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: rs4968104; hg19: chr17-649505; COSMIC: COSV56745287; COSMIC: COSV56745287;