17-745187-G-C

Position:

• chr17-745187-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015721.3(GEMIN4):​c.2856C>G​(p.Asp952Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GEMIN4 NM_015721.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.164

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11287677).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GEMIN4	NM_015721.3	c.2856C>G	p.Asp952Glu	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.2856C>G	p.Asp952Glu	missense_variant	2/2	1	NM_015721.3	ENSP00000321706	P1
GEMIN4	ENST00000576778.1	c.2823C>G	p.Asp941Glu	missense_variant	1/1			ENSP00000459565

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 61

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 27, 2022

The c.2856C>G (p.D952E) alteration is located in exon 2 (coding exon 2) of the GEMIN4 gene. This alteration results from a C to G substitution at nucleotide position 2856, causing the aspartic acid (D) at amino acid position 952 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	7.3
DANN	Benign	0.90
DEOGEN2	Benign	0.010	T;.
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.30
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.58	T;T
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.3	L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.64	N;.
REVEL	Benign	0.038
Sift	Benign	0.35	T;.
Sift4G	Benign	0.61	T;T
Polyphen		0.0010	B;.
Vest4		0.059
MutPred		0.21		Loss of MoRF binding (P = 0.2383);.;
MVP		0.29
MPC		0.13
ClinPred		0.15	T
GERP RS		2.6
Varity_R		0.036
gMVP		0.085

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: rs1001070206; hg19: chr17-648427;