17-744946-G-A

Variant names:

• chr17-744946-G-A
• rs7813
• NM_015721.3:c.3097C>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.3097C>T​(p.Arg1033Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.588 in 1,613,538 control chromosomes in the GnomAD database, including 283,455 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.66 (34059 hom., cov: 34)
  • Exomes 𝑓: 0.58 (249396 hom.)
• Consequence: GEMIN4 NM_015721.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 7.33
• Publications: 110 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.9635254E-6).
• BP6: Variant 17-744946-G-A is Benign according to our data. Variant chr17-744946-G-A is described in ClinVar as Benign. ClinVar VariationId is 1182789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.824 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.3097C>T	p.Arg1033Cys	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.3097C>T	p.Arg1033Cys	missense	Exon 2 of 2	ENSP00000321706.5	P57678
	GEMIN4	ENST00000576778.1	TSL:6	c.3064C>T	p.Arg1022Cys	missense	Exon 1 of 1	ENSP00000459565.1	I3L2C7

Frequencies

GnomAD3 genomes AF: 0.658 AC: 100061 AN: 152088 Hom.: 34005 Cov.: 34

Gnomad AFR AF: 0.831

Gnomad AMI AF: 0.377

Gnomad AMR AF: 0.679

Gnomad ASJ AF: 0.630

Gnomad EAS AF: 0.705

Gnomad SAS AF: 0.639

Gnomad FIN AF: 0.623

Gnomad MID AF: 0.769

Gnomad NFE AF: 0.556

Gnomad OTH AF: 0.660

GnomAD2 exomes AF: 0.627 AC: 155780 AN: 248288 AF XY: 0.624

Gnomad AFR exome AF: 0.833

Gnomad AMR exome AF: 0.691

Gnomad ASJ exome AF: 0.632

Gnomad EAS exome AF: 0.701

Gnomad FIN exome AF: 0.625

Gnomad NFE exome AF: 0.560

Gnomad OTH exome AF: 0.633

GnomAD4 exome AF: 0.580 AC: 848250 AN: 1461332 Hom.: 249396 Cov.: 61 AF XY: 0.582 AC XY: 422987 AN XY: 726946

African (AFR) AF: 0.841 AC: 28152 AN: 33476

American (AMR) AF: 0.689 AC: 30797 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.634 AC: 16553 AN: 26126

East Asian (EAS) AF: 0.676 AC: 26836 AN: 39692

South Asian (SAS) AF: 0.659 AC: 56850 AN: 86236

European-Finnish (FIN) AF: 0.627 AC: 33451 AN: 53330

Middle Eastern (MID) AF: 0.743 AC: 4282 AN: 5764

European-Non Finnish (NFE) AF: 0.553 AC: 614239 AN: 1111682

Other (OTH) AF: 0.614 AC: 37090 AN: 60360

GnomAD4 genome AF: 0.658 AC: 100173 AN: 152206 Hom.: 34059 Cov.: 34 AF XY: 0.660 AC XY: 49111 AN XY: 74404

African (AFR) AF: 0.831 AC: 34527 AN: 41530

American (AMR) AF: 0.679 AC: 10389 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.630 AC: 2187 AN: 3472

East Asian (EAS) AF: 0.704 AC: 3650 AN: 5182

South Asian (SAS) AF: 0.639 AC: 3081 AN: 4824

European-Finnish (FIN) AF: 0.623 AC: 6592 AN: 10582

Middle Eastern (MID) AF: 0.772 AC: 227 AN: 294

European-Non Finnish (NFE) AF: 0.555 AC: 37773 AN: 68000

Other (OTH) AF: 0.663 AC: 1403 AN: 2116

Alfa AF: 0.584 Hom.: 86316

Bravo AF: 0.672

TwinsUK AF: 0.541 AC: 2007

ALSPAC AF: 0.552 AC: 2129

ESP6500AA AF: 0.836 AC: 3317

ESP6500EA AF: 0.563 AC: 4676

ExAC AF: 0.623 AC: 75292

Asia WGS AF: 0.691 AC: 2401 AN: 3478

EpiCase AF: 0.583

EpiControl AF: 0.587

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Neurodevelopmental disorder with microcephaly, cataracts, and renal abnormalities (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.17	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0000020	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	0.90	L
PhyloP100		7.3
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.19
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.011	D
Polyphen		0.99	D
Vest4		0.28
MPC		0.56
ClinPred		0.034	T
GERP RS		5.7
Varity_R		0.29
gMVP		0.22
Mutation Taster		=99/1	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: rs7813; hg19: chr17-648186; COSMIC: COSV56746050; COSMIC: COSV56746050;