chr17-744975-C-T

Position:

chr17-744975-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_015721.3(GEMIN4):c.3068G>A(p.Ser1023Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000295 in 1,613,942 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00030 ( 0 hom. )

Consequence

GEMIN4
NM_015721.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 1.34

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.030442208).

BP6

Variant 17-744975-C-T is Benign according to our data. Variant chr17-744975-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2221084.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GEMIN4	NM_015721.3 linkuse as main transcript	c.3068G>A	p.Ser1023Asn	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 linkuse as main transcript	c.3068G>A	p.Ser1023Asn	missense_variant	2/2	1	NM_015721.3	ENSP00000321706	P1
GEMIN4	ENST00000576778.1 linkuse as main transcript	c.3035G>A	p.Ser1012Asn	missense_variant	1/1			ENSP00000459565

Frequencies

GnomAD3 genomes

AF:

0.000217

AC:

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000441

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000265

AC:

AN:

248970

Hom.:

AF XY:

0.000207

AC XY:

AN XY:

135152

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000580

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000558

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000303

AC:

443

AN:

1461582

Hom.:

Cov.:

AF XY:

0.000278

AC XY:

202

AN XY:

727090

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.0000375

Gnomad4 NFE exome

AF:

0.000380

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.000217

AC:

AN:

152360

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000441

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000395

Hom.:

Bravo

AF:

0.000264

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000361

AC:

ExAC

AF:

0.000322

AC:

EpiCase

AF:

0.000436

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Neurodevelopmental disorder with microcephaly, cataracts, and renal abnormalities

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Jul 19, 2019

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 27, 2022

The c.3068G>A (p.S1023N) alteration is located in exon 2 (coding exon 2) of the GEMIN4 gene. This alteration results from a G to A substitution at nucleotide position 3068, causing the serine (S) at amino acid position 1023 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2022

GEMIN4: BP4 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.73

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.022

T;.

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.62

LIST_S2

Benign

0.54

T;T

M_CAP

Benign

0.0060

MetaRNN

Benign

0.030

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

L;.

MutationTaster

Benign

0.98

N;N

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.60

N;.

REVEL

Benign

0.045

Sift

Benign

0.34

T;.

Sift4G

Benign

0.49

T;T

Polyphen

0.021

B;.

Vest4

0.10

MVP

0.26

MPC

0.12

ClinPred

0.034

GERP RS

3.4

Varity_R

0.051

gMVP

0.25

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over