17-745258-C-T

Position:

• chr17-745258-C-T

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.2785G>A​(p.Asp929Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.834 in 1,610,110 control chromosomes in the GnomAD database, including 561,509 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.87 (57337 hom., cov: 31)
  • Exomes 𝑓: 0.83 (504172 hom.)
• Consequence: GEMIN4 ENST00000319004.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.21

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=1.6844264E-6).
• BP6: Variant 17-745258-C-T is Benign according to our data. Variant chr17-745258-C-T is described in ClinVar as [Benign]. Clinvar id is 1185306.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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GEMIN4	NM_015721.3	c.2785G>A	p.Asp929Asn	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.2785G>A	p.Asp929Asn	missense_variant	2/2	1	NM_015721.3	ENSP00000321706.5
GEMIN4	ENST00000576778.1	c.2752G>A	p.Asp918Asn	missense_variant	1/1	6		ENSP00000459565.1

Frequencies

GnomAD3 genomes AF: 0.866 AC: 131653 AN: 152030 Hom.: 57275 Cov.: 31

Gnomad AFR AF: 0.954

Gnomad AMI AF: 0.786

Gnomad AMR AF: 0.848

Gnomad ASJ AF: 0.904

Gnomad EAS AF: 0.890

Gnomad SAS AF: 0.875

Gnomad FIN AF: 0.814

Gnomad MID AF: 0.896

Gnomad NFE AF: 0.821

Gnomad OTH AF: 0.882

GnomAD3 exomes AF: 0.846 AC: 205048 AN: 242470 Hom.: 86940 AF XY: 0.846 AC XY: 111789 AN XY: 132084

Gnomad AFR exome AF: 0.957

Gnomad AMR exome AF: 0.813

Gnomad ASJ exome AF: 0.908

Gnomad EAS exome AF: 0.884

Gnomad SAS exome AF: 0.868

Gnomad FIN exome AF: 0.819

Gnomad NFE exome AF: 0.827

Gnomad OTH exome AF: 0.859

GnomAD4 exome AF: 0.831 AC: 1211267 AN: 1457962 Hom.: 504172 Cov.: 51 AF XY: 0.832 AC XY: 602897 AN XY: 725036

Gnomad4 AFR exome AF: 0.959

Gnomad4 AMR exome AF: 0.820

Gnomad4 ASJ exome AF: 0.907

Gnomad4 EAS exome AF: 0.893

Gnomad4 SAS exome AF: 0.866

Gnomad4 FIN exome AF: 0.820

Gnomad4 NFE exome AF: 0.819

Gnomad4 OTH exome AF: 0.859

GnomAD4 genome AF: 0.866 AC: 131776 AN: 152148 Hom.: 57337 Cov.: 31 AF XY: 0.866 AC XY: 64434 AN XY: 74386

Gnomad4 AFR AF: 0.954

Gnomad4 AMR AF: 0.848

Gnomad4 ASJ AF: 0.904

Gnomad4 EAS AF: 0.890

Gnomad4 SAS AF: 0.874

Gnomad4 FIN AF: 0.814

Gnomad4 NFE AF: 0.821

Gnomad4 OTH AF: 0.884

Alfa AF: 0.839 Hom.: 129787

Bravo AF: 0.874

TwinsUK AF: 0.815 AC: 3022

ALSPAC AF: 0.821 AC: 3164

ESP6500AA AF: 0.955 AC: 3673

ESP6500EA AF: 0.826 AC: 6829

ExAC AF: 0.843 AC: 101807

Asia WGS AF: 0.905 AC: 3146 AN: 3478

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: 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	0.065
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	7.0
DANN	Benign	0.79
DEOGEN2	Benign	0.020	T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.20	T;T
MetaRNN	Benign	0.0000017	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.76	N;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.42	T
PROVEAN	Benign	0.27	N;.
REVEL	Benign	0.089
Sift	Benign	1.0	T;.
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;.
Vest4		0.039
MPC		0.13
ClinPred		0.00085	T
GERP RS		4.7
Varity_R		0.043
gMVP		0.073

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: rs2740349; hg19: chr17-648498; COSMIC: COSV56746845; COSMIC: COSV56746845;