rs2740348

Variant names:

• chr17-746695-G-C
• rs2740348
• NM_015721.3:c.1348C>G

Your query was ambiguous. Multiple possible variants found:

• chr17-746695-G-C
• chr17-746695-G-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.1348C>G​(p.Gln450Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.835 in 1,613,310 control chromosomes in the GnomAD database, including 563,156 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 0.87 (57341 hom., cov: 30)
  • Exomes 𝑓: 0.83 (505815 hom.)
• Consequence: GEMIN4 NM_015721.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.23
• Publications: 73 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=7.732567E-7).
• BP6: Variant 17-746695-G-C is Benign according to our data. Variant chr17-746695-G-C is described in ClinVar as Benign. ClinVar VariationId is 1185310.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.946 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.1348C>G	p.Gln450Glu	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.1348C>G	p.Gln450Glu	missense	Exon 2 of 2	ENSP00000321706.5	P57678
	GEMIN4	ENST00000576778.1	TSL:6	c.1315C>G	p.Gln439Glu	missense	Exon 1 of 1	ENSP00000459565.1	I3L2C7
	GEMIN4	ENST00000437269.1	TSL:2	c.*531C>G		3_prime_UTR	Exon 3 of 3	ENSP00000392460.1	E7EN12

Frequencies

GnomAD3 genomes AF: 0.866 AC: 131644 AN: 151984 Hom.: 57279 Cov.: 30

Gnomad AFR AF: 0.954

Gnomad AMI AF: 0.785

Gnomad AMR AF: 0.848

Gnomad ASJ AF: 0.904

Gnomad EAS AF: 0.890

Gnomad SAS AF: 0.879

Gnomad FIN AF: 0.813

Gnomad MID AF: 0.896

Gnomad NFE AF: 0.821

Gnomad OTH AF: 0.883

GnomAD2 exomes AF: 0.847 AC: 210894 AN: 249042 AF XY: 0.848

Gnomad AFR exome AF: 0.957

Gnomad AMR exome AF: 0.814

Gnomad ASJ exome AF: 0.909

Gnomad EAS exome AF: 0.883

Gnomad FIN exome AF: 0.819

Gnomad NFE exome AF: 0.828

Gnomad OTH exome AF: 0.860

GnomAD4 exome AF: 0.831 AC: 1214542 AN: 1461208 Hom.: 505815 Cov.: 72 AF XY: 0.832 AC XY: 604843 AN XY: 726898

African (AFR) AF: 0.959 AC: 32117 AN: 33480

American (AMR) AF: 0.820 AC: 36667 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.907 AC: 23711 AN: 26136

East Asian (EAS) AF: 0.893 AC: 35455 AN: 39700

South Asian (SAS) AF: 0.870 AC: 75063 AN: 86256

European-Finnish (FIN) AF: 0.820 AC: 43438 AN: 52992

Middle Eastern (MID) AF: 0.908 AC: 5237 AN: 5768

European-Non Finnish (NFE) AF: 0.819 AC: 910984 AN: 1111786

Other (OTH) AF: 0.859 AC: 51870 AN: 60370

GnomAD4 genome AF: 0.866 AC: 131767 AN: 152102 Hom.: 57341 Cov.: 30 AF XY: 0.866 AC XY: 64417 AN XY: 74348

African (AFR) AF: 0.954 AC: 39617 AN: 41512

American (AMR) AF: 0.848 AC: 12956 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.904 AC: 3138 AN: 3470

East Asian (EAS) AF: 0.890 AC: 4581 AN: 5150

South Asian (SAS) AF: 0.879 AC: 4233 AN: 4818

European-Finnish (FIN) AF: 0.813 AC: 8605 AN: 10580

Middle Eastern (MID) AF: 0.901 AC: 265 AN: 294

European-Non Finnish (NFE) AF: 0.821 AC: 55794 AN: 67982

Other (OTH) AF: 0.884 AC: 1864 AN: 2108

Alfa AF: 0.830 Hom.: 13106

Bravo AF: 0.874

TwinsUK AF: 0.815 AC: 3023

ALSPAC AF: 0.821 AC: 3164

ESP6500AA AF: 0.955 AC: 3789

ESP6500EA AF: 0.826 AC: 6842

ExAC AF: 0.848 AC: 102396

Asia WGS AF: 0.906 AC: 3151 AN: 3478

EpiCase AF: 0.843

EpiControl AF: 0.847

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	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	0.045
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	11
DANN	Benign	0.67
DEOGEN2	Benign	0.0093	T
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.057	T
MetaRNN	Benign	7.7e-7	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-2.3	N
PhyloP100		2.2
PrimateAI	Benign	0.35	T
PROVEAN	Benign	1.0	N
REVEL	Benign	0.082
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.023
MPC		0.14
ClinPred		0.0052	T
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.027
gMVP		0.091
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: rs2740348; hg19: chr17-649935; COSMIC: COSV56746214; COSMIC: COSV56746214;