rs7813

Positions:

• chr17-744946-G-A
• chr17-744946-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000319004.6(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 (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.66 (34059 hom., cov: 34)
  • Exomes 𝑓: 0.58 (249396 hom.)
• Consequence: GEMIN4 ENST00000319004.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 7.33

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GEMIN4	NM_015721.3	c.3097C>T	p.Arg1033Cys	missense_variant	2/2	ENST00000319004.6	NP_056536.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GEMIN4	ENST00000319004.6	c.3097C>T	p.Arg1033Cys	missense_variant	2/2	1	NM_015721.3	ENSP00000321706	P1
GEMIN4	ENST00000576778.1	c.3064C>T	p.Arg1022Cys	missense_variant	1/1			ENSP00000459565

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

GnomAD3 exomes AF: 0.627 AC: 155780 AN: 248288 Hom.: 49784 AF XY: 0.624 AC XY: 84063 AN XY: 134822

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 SAS exome AF: 0.657

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

Gnomad4 AFR exome AF: 0.841

Gnomad4 AMR exome AF: 0.689

Gnomad4 ASJ exome AF: 0.634

Gnomad4 EAS exome AF: 0.676

Gnomad4 SAS exome AF: 0.659

Gnomad4 FIN exome AF: 0.627

Gnomad4 NFE exome AF: 0.553

Gnomad4 OTH exome AF: 0.614

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

Gnomad4 AFR AF: 0.831

Gnomad4 AMR AF: 0.679

Gnomad4 ASJ AF: 0.630

Gnomad4 EAS AF: 0.704

Gnomad4 SAS AF: 0.639

Gnomad4 FIN AF: 0.623

Gnomad4 NFE AF: 0.555

Gnomad4 OTH AF: 0.663

Alfa AF: 0.583 Hom.: 37384

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

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 03, 2020	This variant is associated with the following publications: (PMID: 19047128, 21766210, 20732906, 21118967) -

Neurodevelopmental disorder with microcephaly, cataracts, and renal abnormalities Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

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;T
MetaRNN	Benign	0.0000020	T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	0.90	L;.
MutationTaster	Benign	0.000018	P;P
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-3.2	D;.
REVEL	Benign	0.19
Sift	Uncertain	0.0050	D;.
Sift4G	Uncertain	0.011	D;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs7813; hg19: chr17-648186; COSMIC: COSV56746050; COSMIC: COSV56746050;