chr17-746307-G-C

Position:

• chr17-746307-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000319004.6(GEMIN4):​c.1736C>G​(p.Ala579Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.588 in 1,613,454 control chromosomes in the GnomAD database, including 283,902 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.66 (34134 hom., cov: 32)
  • Exomes 𝑓: 0.58 (249768 hom.)
• Consequence: GEMIN4 ENST00000319004.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• 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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.4544598E-6).
• BP6: Variant 17-746307-G-C is Benign according to our data. Variant chr17-746307-G-C is described in ClinVar as [Benign]. Clinvar id is 1185309.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.827 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GEMIN4	NM_015721.3	c.1736C>G	p.Ala579Gly	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>G	p.Ala579Gly	missense_variant	2/2	1	NM_015721.3	ENSP00000321706	P1
GEMIN4	ENST00000576778.1	c.1703C>G	p.Ala568Gly	missense_variant	1/1			ENSP00000459565

Frequencies

GnomAD3 genomes AF: 0.659 AC: 100097 AN: 151908 Hom.: 34079 Cov.: 32

Gnomad AFR AF: 0.834

Gnomad AMI AF: 0.377

Gnomad AMR AF: 0.679

Gnomad ASJ AF: 0.630

Gnomad EAS AF: 0.706

Gnomad SAS AF: 0.642

Gnomad FIN AF: 0.623

Gnomad MID AF: 0.766

Gnomad NFE AF: 0.555

Gnomad OTH AF: 0.660

GnomAD3 exomes AF: 0.628 AC: 156240 AN: 248734 Hom.: 50054 AF XY: 0.624 AC XY: 84303 AN XY: 135026

Gnomad AFR exome AF: 0.837

Gnomad AMR exome AF: 0.691

Gnomad ASJ exome AF: 0.633

Gnomad EAS exome AF: 0.702

Gnomad SAS exome AF: 0.661

Gnomad FIN exome AF: 0.625

Gnomad NFE exome AF: 0.560

Gnomad OTH exome AF: 0.634

GnomAD4 exome AF: 0.581 AC: 848761 AN: 1461428 Hom.: 249768 Cov.: 77 AF XY: 0.582 AC XY: 423312 AN XY: 726976

Gnomad4 AFR exome AF: 0.845

Gnomad4 AMR exome AF: 0.690

Gnomad4 ASJ exome AF: 0.634

Gnomad4 EAS exome AF: 0.676

Gnomad4 SAS exome AF: 0.663

Gnomad4 FIN exome AF: 0.627

Gnomad4 NFE exome AF: 0.552

Gnomad4 OTH exome AF: 0.615

GnomAD4 genome AF: 0.659 AC: 100211 AN: 152026 Hom.: 34134 Cov.: 32 AF XY: 0.661 AC XY: 49104 AN XY: 74288

Gnomad4 AFR AF: 0.835

Gnomad4 AMR AF: 0.680

Gnomad4 ASJ AF: 0.630

Gnomad4 EAS AF: 0.706

Gnomad4 SAS AF: 0.642

Gnomad4 FIN AF: 0.623

Gnomad4 NFE AF: 0.555

Gnomad4 OTH AF: 0.663

Alfa AF: 0.589 Hom.: 8710

Bravo AF: 0.673

TwinsUK AF: 0.540 AC: 2003

ALSPAC AF: 0.553 AC: 2132

ESP6500AA AF: 0.832 AC: 3341

ESP6500EA AF: 0.563 AC: 4705

ExAC AF: 0.624 AC: 75429

Asia WGS AF: 0.692 AC: 2403 AN: 3478

EpiCase AF: 0.583

EpiControl AF: 0.585

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 16, 2020	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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	0.12
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T;.
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.66	T;T
MetaRNN	Benign	0.0000015	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M;.
MutationTaster	Benign	9.7e-9	P;P
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.4	D;.
REVEL	Uncertain	0.33
Sift	Uncertain	0.022	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.31
MPC		0.60
ClinPred		0.018	T
GERP RS		5.8
Varity_R		0.51
gMVP		0.38

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; COSMIC: COSV56746063; COSMIC: COSV56746063;