NM_015721.3:c.2216T>C

Variant names:

• chr17-745827-A-G
• rs1062923
• NM_015721.3:c.2216T>C

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.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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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
• Publications: 50 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=0.0043025613).
• BP6: Variant 17-745827-A-G is Benign according to our data. Variant chr17-745827-A-G is described in ClinVar as Benign. ClinVar VariationId 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.

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.2216T>C	p.Ile739Thr	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.2216T>C	p.Ile739Thr	missense	Exon 2 of 2	ENSP00000321706.5	P57678
	GEMIN4	ENST00000576778.1	TSL:6	c.2183T>C	p.Ile728Thr	missense	Exon 1 of 1	ENSP00000459565.1	I3L2C7

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

GnomAD2 exomes AF: 0.130 AC: 32146 AN: 247698 AF XY: 0.135

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 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

African (AFR) AF: 0.0272 AC: 909 AN: 33464

American (AMR) AF: 0.0714 AC: 3186 AN: 44650

Ashkenazi Jewish (ASJ) AF: 0.192 AC: 5007 AN: 26116

East Asian (EAS) AF: 0.000731 AC: 29 AN: 39694

South Asian (SAS) AF: 0.124 AC: 10681 AN: 86186

European-Finnish (FIN) AF: 0.195 AC: 10282 AN: 52722

Middle Eastern (MID) AF: 0.190 AC: 1092 AN: 5760

European-Non Finnish (NFE) AF: 0.172 AC: 191629 AN: 1111614

Other (OTH) AF: 0.152 AC: 9165 AN: 60344

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

African (AFR) AF: 0.0313 AC: 1299 AN: 41568

American (AMR) AF: 0.111 AC: 1697 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.194 AC: 673 AN: 3470

East Asian (EAS) AF: 0.00136 AC: 7 AN: 5162

South Asian (SAS) AF: 0.111 AC: 535 AN: 4828

European-Finnish (FIN) AF: 0.184 AC: 1941 AN: 10572

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.169 AC: 11458 AN: 67958

Other (OTH) AF: 0.122 AC: 258 AN: 2114

Alfa AF: 0.148 Hom.: 6978

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	GEMIN4-related disorder (1)
-	-	1	Neurodevelopmental disorder with microcephaly, cataracts, and renal abnormalities (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0043	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.49	N
PhyloP100		1.1
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.063
Sift	Benign	0.14	T
Sift4G	Benign	0.23	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
Mutation Taster		=97/3	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: rs1062923; hg19: chr17-649067; COSMIC: COSV56746058; COSMIC: COSV56746058;