rs2740348

Positions:

• chr17-746695-G-C
• chr17-746695-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_015721.3(GEMIN4):​c.1348C>G​(p.Gln450Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.835 in 1,613,310 control chromosomes in the GnomAD database, including 563,156 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 (57341 hom., cov: 30)
  • Exomes 𝑓: 0.83 (505815 hom.)
• Consequence: GEMIN4 NM_015721.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.23

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.732567E-7).
• BP6: Variant 17-746695-G-C is Benign according to our data. Variant chr17-746695-G-C is described in ClinVar as [Benign]. Clinvar id is 1185310.Status of the report is criteria_provided_single_submitter, 1 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	UniProt
GEMIN4	NM_015721.3	c.1348C>G	p.Gln450Glu	missense_variant	2/2	ENST00000319004.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GEMIN4	ENST00000319004.6	c.1348C>G	p.Gln450Glu	missense_variant	2/2	1	NM_015721.3	P1
GEMIN4	ENST00000576778.1	c.1315C>G	p.Gln439Glu	missense_variant	1/1
GEMIN4	ENST00000437269.1	c.*531C>G		3_prime_UTR_variant	3/3	2

Frequencies

GnomAD3 genomes AF: 0.866 AC: 131644 AN: 151984 Hom.: 57279 Cov.: 30

Gnomad AFR AF: 0.954

Gnomad AMI AF: 0.785

Gnomad AMR AF: 0.848

Gnomad ASJ AF: 0.904

Gnomad EAS AF: 0.890

Gnomad SAS AF: 0.879

Gnomad FIN AF: 0.813

Gnomad MID AF: 0.896

Gnomad NFE AF: 0.821

Gnomad OTH AF: 0.883

GnomAD3 exomes AF: 0.847 AC: 210894 AN: 249042 Hom.: 89606 AF XY: 0.848 AC XY: 114600 AN XY: 135176

Gnomad AFR exome AF: 0.957

Gnomad AMR exome AF: 0.814

Gnomad ASJ exome AF: 0.909

Gnomad EAS exome AF: 0.883

Gnomad SAS exome AF: 0.873

Gnomad FIN exome AF: 0.819

Gnomad NFE exome AF: 0.828

Gnomad OTH exome AF: 0.860

GnomAD4 exome AF: 0.831 AC: 1214542 AN: 1461208 Hom.: 505815 Cov.: 72 AF XY: 0.832 AC XY: 604843 AN XY: 726898

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: 0.870

Gnomad4 FIN exome AF: 0.820

Gnomad4 NFE exome AF: 0.819

Gnomad4 OTH exome AF: 0.859

GnomAD4 genome AF: 0.866 AC: 131767 AN: 152102 Hom.: 57341 Cov.: 30 AF XY: 0.866 AC XY: 64417 AN XY: 74348

Gnomad4 AFR AF: 0.954

Gnomad4 AMR AF: 0.848

Gnomad4 ASJ AF: 0.904

Gnomad4 EAS AF: 0.890

Gnomad4 SAS AF: 0.879

Gnomad4 FIN AF: 0.813

Gnomad4 NFE AF: 0.821

Gnomad4 OTH AF: 0.884

Alfa AF: 0.830 Hom.: 13106

Bravo AF: 0.874

TwinsUK AF: 0.815 AC: 3023

ALSPAC AF: 0.821 AC: 3164

ESP6500AA AF: 0.955 AC: 3789

ESP6500EA AF: 0.826 AC: 6842

ExAC AF: 0.848 AC: 102396

Asia WGS AF: 0.906 AC: 3151 AN: 3478

EpiCase AF: 0.843

EpiControl AF: 0.847

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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	0.045
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	11
DANN	Benign	0.67
DEOGEN2	Benign	0.0093	T;.
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.057	T;T
MetaRNN	Benign	7.7e-7	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-2.3	N;.
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.35	T
PROVEAN	Benign	1.0	N;.
REVEL	Benign	0.082
Sift	Benign	1.0	T;.
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;.
Vest4		0.023
MPC		0.14
ClinPred		0.0052	T
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.027
gMVP		0.091

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: rs2740348; hg19: chr17-649935; COSMIC: COSV56746214; COSMIC: COSV56746214;