rs910925

Positions:

• chr17-746307-G-A
• chr17-746307-G-C
• chr17-746307-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_015721.3(GEMIN4):​c.1736C>T​(p.Ala579Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A579G) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GEMIN4 NM_015721.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.85

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.866

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GEMIN4	NM_015721.3	c.1736C>T	p.Ala579Val	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.1736C>T	p.Ala579Val	missense_variant	2/2	1	NM_015721.3	ENSP00000321706	P1
GEMIN4	ENST00000576778.1	c.1703C>T	p.Ala568Val	missense_variant	1/1			ENSP00000459565

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 77

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.29	T;.
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.022	T
MetaRNN	Pathogenic	0.87	D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	M;.
MutationTaster	Benign	8.1e-9	P;P
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.4	D;.
REVEL	Uncertain	0.58
Sift	Uncertain	0.0030	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.72
MutPred		0.63		Gain of ubiquitination at K576 (P = 0.0581);.;
MVP		0.63
MPC		0.60
ClinPred		0.97	D
GERP RS		5.8
Varity_R		0.59
gMVP		0.47

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: rs910925; hg19: chr17-649547;