rs730882219

Variant names:

• chr17-745591-A-G
• rs730882219
• NM_015721.3:c.2452T>C

Your query was ambiguous. Multiple possible variants found:

• chr17-745591-A-G
• chr17-745591-A-C

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_015721.3(GEMIN4):​c.2452T>C​(p.Trp818Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,459,034 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: GEMIN4 NM_015721.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.43
• Publications: 3 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: Pathogenic. The variant received 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.962
• PP5: Variant 17-745591-A-G is Pathogenic according to our data. Variant chr17-745591-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 183310.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.2452T>C	p.Trp818Arg	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.2452T>C	p.Trp818Arg	missense	Exon 2 of 2	ENSP00000321706.5	P57678
	GEMIN4	ENST00000576778.1	TSL:6	c.2419T>C	p.Trp807Arg	missense	Exon 1 of 1	ENSP00000459565.1	I3L2C7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000123 AC: 3 AN: 243694 AF XY: 0.0000226

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1459034 Hom.: 0 Cov.: 51 AF XY: 0.00000689 AC XY: 5 AN XY: 725642

African (AFR) AF: 0.00 AC: 0 AN: 33430

American (AMR) AF: 0.00 AC: 0 AN: 44390

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26004

East Asian (EAS) AF: 0.00 AC: 0 AN: 39646

South Asian (SAS) AF: 0.0000699 AC: 6 AN: 85850

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52470

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111158

Other (OTH) AF: 0.00 AC: 0 AN: 60320

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000827 AC: 1

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Neurodevelopmental disorder with microcephaly, cataracts, and renal abnormalities (3)
1	-	-	Developmental cataract;C0557874:Global developmental delay;C4551563:Microcephaly;CN228291:Severe dystonia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.093	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.75	T
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		7.4
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-11	D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.79		Loss of catalytic residue at L816 (P = 0.0033)
MVP		0.70
MPC		0.81
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.95
gMVP		0.89
Mutation Taster		=21/79	disease causing (ClinVar)

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: rs730882219; hg19: chr17-648831;