17-746695-G-T

Variant names:

• chr17-746695-G-T
• rs2740348
• NM_015721.3:c.1348C>A

Variant summary

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

The NM_015721.3(GEMIN4):​c.1348C>A​(p.Gln450Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,010 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 30)
• Consequence: GEMIN4 NM_015721.3 missense
• Clinical Significance: Not reported in ClinVar
• 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 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=0.08053073).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GEMIN4	NM_015721.3	c.1348C>A	p.Gln450Lys	missense_variant	Exon 2 of 2	ENST00000319004.6	NP_056536.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GEMIN4	ENST00000319004.6	c.1348C>A	p.Gln450Lys	missense_variant	Exon 2 of 2	1	NM_015721.3	ENSP00000321706.5
GEMIN4	ENST00000576778.1	c.1315C>A	p.Gln439Lys	missense_variant	Exon 1 of 1	6		ENSP00000459565.1
GEMIN4	ENST00000437269	c.*531C>A		3_prime_UTR_variant	Exon 3 of 3	2		ENSP00000392460.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152010 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000242

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 72

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152010 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 74230

Gnomad4 AFR AF: 0.0000242

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: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	13
DANN	Benign	0.75
DEOGEN2	Benign	0.011	T;.
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.14	T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.081	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	N;.
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.89	N;.
REVEL	Benign	0.077
Sift	Benign	0.20	T;.
Sift4G	Benign	0.19	T;T
Polyphen		0.0	B;.
Vest4		0.042
MutPred		0.32		Gain of catalytic residue at Q450 (P = 0.0267);.;
MVP		0.21
MPC		0.17
ClinPred		0.090	T
GERP RS		6.1
Varity_R		0.032
gMVP		0.17

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;