rs3744741

Positions:

• chr17-745992-C-T

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.2051G>A​(p.Arg684Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.157 in 1,613,082 control chromosomes in the GnomAD database, including 23,573 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 0.21 (3920 hom., cov: 32)
  • Exomes 𝑓: 0.15 (19653 hom.)
• Consequence: GEMIN4 NM_015721.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.502

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=0.0039718747).
• BP6: Variant 17-745992-C-T is Benign according to our data. Variant chr17-745992-C-T is described in ClinVar as [Benign]. Clinvar id is 1185308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.319 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GEMIN4	NM_015721.3	c.2051G>A	p.Arg684Gln	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.2051G>A	p.Arg684Gln	missense_variant	2/2	1	NM_015721.3	ENSP00000321706.5
GEMIN4	ENST00000576778.1	c.2018G>A	p.Arg673Gln	missense_variant	1/1	6		ENSP00000459565.1

Frequencies

GnomAD3 genomes AF: 0.206 AC: 31356 AN: 151958 Hom.: 3906 Cov.: 32

Gnomad AFR AF: 0.319

Gnomad AMI AF: 0.0395

Gnomad AMR AF: 0.267

Gnomad ASJ AF: 0.104

Gnomad EAS AF: 0.332

Gnomad SAS AF: 0.258

Gnomad FIN AF: 0.124

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.132

Gnomad OTH AF: 0.204

GnomAD3 exomes AF: 0.199 AC: 49475 AN: 248362 Hom.: 6023 AF XY: 0.194 AC XY: 26128 AN XY: 134832

Gnomad AFR exome AF: 0.324

Gnomad AMR exome AF: 0.325

Gnomad ASJ exome AF: 0.111

Gnomad EAS exome AF: 0.335

Gnomad SAS exome AF: 0.255

Gnomad FIN exome AF: 0.128

Gnomad NFE exome AF: 0.130

Gnomad OTH exome AF: 0.171

GnomAD4 exome AF: 0.152 AC: 222368 AN: 1461006 Hom.: 19653 Cov.: 63 AF XY: 0.154 AC XY: 112131 AN XY: 726800

Gnomad4 AFR exome AF: 0.319

Gnomad4 AMR exome AF: 0.317

Gnomad4 ASJ exome AF: 0.109

Gnomad4 EAS exome AF: 0.265

Gnomad4 SAS exome AF: 0.258

Gnomad4 FIN exome AF: 0.127

Gnomad4 NFE exome AF: 0.129

Gnomad4 OTH exome AF: 0.174

GnomAD4 genome AF: 0.207 AC: 31415 AN: 152076 Hom.: 3920 Cov.: 32 AF XY: 0.208 AC XY: 15463 AN XY: 74336

Gnomad4 AFR AF: 0.318

Gnomad4 AMR AF: 0.268

Gnomad4 ASJ AF: 0.104

Gnomad4 EAS AF: 0.332

Gnomad4 SAS AF: 0.259

Gnomad4 FIN AF: 0.124

Gnomad4 NFE AF: 0.132

Gnomad4 OTH AF: 0.212

Alfa AF: 0.150 Hom.: 4099

Bravo AF: 0.220

TwinsUK AF: 0.128 AC: 475

ALSPAC AF: 0.121 AC: 468

ESP6500AA AF: 0.304 AC: 1197

ESP6500EA AF: 0.126 AC: 1049

ExAC AF: 0.196 AC: 23660

Asia WGS AF: 0.342 AC: 1185 AN: 3478

EpiCase AF: 0.135

EpiControl AF: 0.139

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 15, 2020	This variant is associated with the following publications: (PMID: 23322153) -

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.36
DANN	Benign	0.64
DEOGEN2	Benign	0.0089	T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.55	T;T
MetaRNN	Benign	0.0040	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.0	N;.
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.020	N;.
REVEL	Benign	0.011
Sift	Benign	0.58	T;.
Sift4G	Benign	0.58	T;T
Polyphen		0.37	B;.
Vest4		0.027
MPC		0.18
ClinPred		0.0021	T
GERP RS		0.42
Varity_R		0.014
gMVP		0.062

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: rs3744741; hg19: chr17-649232; COSMIC: COSV56745132; COSMIC: COSV56745132;