chr17-746265-T-A

Variant names:

• chr17-746265-T-A
• rs4968104
• NM_015721.3:c.1778A>T

Variant summary

Our verdict is Benign. The variant received -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. 14/21 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:3
• Conservation: PhyloP100: 0.0140
• Publications: 46 publications found

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]

GEMIN4 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with microcephaly, cataracts, and renal abnormalities

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015721.3. 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
	GEMIN4	NM_015721.3	MANE Select	c.1778A>T	p.Glu593Val	missense	Exon 2 of 2	NP_056536.2	P57678

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GEMIN4	ENST00000319004.6	TSL:1 MANE Select	c.1778A>T	p.Glu593Val	missense	Exon 2 of 2	ENSP00000321706.5	P57678
	GEMIN4	ENST00000576778.1	TSL:6	c.1745A>T	p.Glu582Val	missense	Exon 1 of 1	ENSP00000459565.1	I3L2C7

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

GnomAD2 exomes AF: 0.204 AC: 50811 AN: 249018 AF XY: 0.209

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 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

African (AFR) AF: 0.0855 AC: 2864 AN: 33480

American (AMR) AF: 0.125 AC: 5599 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.243 AC: 6361 AN: 26136

East Asian (EAS) AF: 0.145 AC: 5747 AN: 39700

South Asian (SAS) AF: 0.194 AC: 16763 AN: 86258

European-Finnish (FIN) AF: 0.191 AC: 10161 AN: 53170

Middle Eastern (MID) AF: 0.146 AC: 840 AN: 5768

European-Non Finnish (NFE) AF: 0.259 AC: 287466 AN: 1111844

Other (OTH) AF: 0.232 AC: 14015 AN: 60370

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

African (AFR) AF: 0.0907 AC: 3765 AN: 41526

American (AMR) AF: 0.159 AC: 2425 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.244 AC: 846 AN: 3472

East Asian (EAS) AF: 0.124 AC: 642 AN: 5168

South Asian (SAS) AF: 0.219 AC: 1055 AN: 4822

European-Finnish (FIN) AF: 0.188 AC: 1991 AN: 10572

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.257 AC: 17436 AN: 67974

Other (OTH) AF: 0.208 AC: 440 AN: 2112

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	GEMIN4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0046	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		0.014
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.14
Sift	Benign	0.14	T
Sift4G	Benign	0.14	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
Mutation Taster		=100/0	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: rs4968104; hg19: chr17-649505; COSMIC: COSV56745287; COSMIC: COSV56745287;