rs1062923

Positions:

• chr17-745827-A-G

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.2216T>C​(p.Ile739Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.155 in 1,612,720 control chromosomes in the GnomAD database, including 21,350 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.12 (1402 hom., cov: 32)
  • Exomes 𝑓: 0.16 (19948 hom.)
• Consequence: GEMIN4 NM_015721.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.09

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=0.0043025613).
• BP6: Variant 17-745827-A-G is Benign according to our data. Variant chr17-745827-A-G is described in ClinVar as [Benign]. Clinvar id is 1185307.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.166 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GEMIN4	NM_015721.3	c.2216T>C	p.Ile739Thr	missense_variant	2/2	ENST00000319004.6	NP_056536.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GEMIN4	ENST00000319004.6	c.2216T>C	p.Ile739Thr	missense_variant	2/2	1	NM_015721.3	ENSP00000321706	P1
GEMIN4	ENST00000576778.1	c.2183T>C	p.Ile728Thr	missense_variant	1/1			ENSP00000459565

Frequencies

GnomAD3 genomes AF: 0.119 AC: 18088 AN: 152052 Hom.: 1401 Cov.: 32

Gnomad AFR AF: 0.0313

Gnomad AMI AF: 0.171

Gnomad AMR AF: 0.111

Gnomad ASJ AF: 0.194

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.111

Gnomad FIN AF: 0.184

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.169

Gnomad OTH AF: 0.124

GnomAD3 exomes AF: 0.130 AC: 32146 AN: 247698 Hom.: 2504 AF XY: 0.135 AC XY: 18211 AN XY: 134608

Gnomad AFR exome AF: 0.0280

Gnomad AMR exome AF: 0.0692

Gnomad ASJ exome AF: 0.182

Gnomad EAS exome AF: 0.000613

Gnomad SAS exome AF: 0.125

Gnomad FIN exome AF: 0.190

Gnomad NFE exome AF: 0.167

Gnomad OTH exome AF: 0.145

GnomAD4 exome AF: 0.159 AC: 231980 AN: 1460550 Hom.: 19948 Cov.: 59 AF XY: 0.159 AC XY: 115203 AN XY: 726520

Gnomad4 AFR exome AF: 0.0272

Gnomad4 AMR exome AF: 0.0714

Gnomad4 ASJ exome AF: 0.192

Gnomad4 EAS exome AF: 0.000731

Gnomad4 SAS exome AF: 0.124

Gnomad4 FIN exome AF: 0.195

Gnomad4 NFE exome AF: 0.172

Gnomad4 OTH exome AF: 0.152

GnomAD4 genome AF: 0.119 AC: 18079 AN: 152170 Hom.: 1402 Cov.: 32 AF XY: 0.118 AC XY: 8801 AN XY: 74400

Gnomad4 AFR AF: 0.0313

Gnomad4 AMR AF: 0.111

Gnomad4 ASJ AF: 0.194

Gnomad4 EAS AF: 0.00136

Gnomad4 SAS AF: 0.111

Gnomad4 FIN AF: 0.184

Gnomad4 NFE AF: 0.169

Gnomad4 OTH AF: 0.122

Alfa AF: 0.157 Hom.: 5256

Bravo AF: 0.109

TwinsUK AF: 0.167 AC: 619

ALSPAC AF: 0.165 AC: 636

ESP6500AA AF: 0.0342 AC: 134

ESP6500EA AF: 0.169 AC: 1404

ExAC AF: 0.127 AC: 15391

Asia WGS AF: 0.0490 AC: 170 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurodevelopmental disorder with microcephaly, cataracts, and renal abnormalities Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

GEMIN4-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 21, 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

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	4.3
DANN	Benign	0.75
DEOGEN2	Benign	0.029	T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.63	T;T
MetaRNN	Benign	0.0043	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.49	N;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-2.1	N;.
REVEL	Benign	0.063
Sift	Benign	0.14	T;.
Sift4G	Benign	0.23	T;T
Polyphen		0.0010	B;.
Vest4		0.035
MPC		0.17
ClinPred		0.014	T
GERP RS		-2.2
Varity_R		0.086
gMVP		0.20

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: rs1062923; hg19: chr17-649067; COSMIC: COSV56746058; COSMIC: COSV56746058;