rs61749643

chr5-154899279-G-Achr5-154899279-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_015465.5(GEMIN5):c.3046C>T(p.Arg1016Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00704 in 1,611,648 control chromosomes in the GnomAD database, including 58 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0045 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0073 (56 hom.)
• Consequence: GEMIN5 NM_015465.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 6.14

Genes affected

GEMIN5 (HGNC:20043): (gem nuclear organelle associated protein 5) This gene encodes a WD repeat protein that is a component of the survival of motor neurons (SMN) complex. The SMN complex plays a critical role in mRNA splicing through the assembly of spliceosomal small nuclear ribonucleoproteins (snRNPs), and may also mediate the assembly and transport of other classes of ribonucleoproteins. The encoded protein is the snRNA-binding component of the SMN complex. Dysregulation of this gene may play a role in alternative mRNA splicing and tumor cell motility. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Nov 2011]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01176995).
• BP6: Variant 5-154899279-G-A is Benign according to our data. Variant chr5-154899279-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 562188.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00454 (692/152298) while in subpopulation NFE AF= 0.00722 (491/68022). AF 95% confidence interval is 0.00669. There are 2 homozygotes in gnomad4. There are 314 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GEMIN5	NM_015465.5	c.3046C>T	p.Arg1016Cys	missense_variant	22/28	ENST00000285873.8
GEMIN5	NM_001252156.2	c.3043C>T	p.Arg1015Cys	missense_variant	22/28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GEMIN5	ENST00000285873.8	c.3046C>T	p.Arg1016Cys	missense_variant	22/28	1	NM_015465.5	P1

Frequencies

GnomAD3 genomes AF: 0.00454 AC: 691 AN: 152180 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00208

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00556

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00722

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00460 AC: 1149 AN: 249516 Hom.: 5 AF XY: 0.00463 AC XY: 624 AN XY: 134888

Gnomad AFR exome AF: 0.00216

Gnomad AMR exome AF: 0.00433

Gnomad ASJ exome AF: 0.00280

Gnomad EAS exome AF: 0.0000548

Gnomad SAS exome AF: 0.00211

Gnomad FIN exome AF: 0.000324

Gnomad NFE exome AF: 0.00737

Gnomad OTH exome AF: 0.00542

GnomAD4 exome AF: 0.00730 AC: 10654 AN: 1459350 Hom.: 56 Cov.: 30 AF XY: 0.00709 AC XY: 5144 AN XY: 725854

Gnomad4 AFR exome AF: 0.00153

Gnomad4 AMR exome AF: 0.00457

Gnomad4 ASJ exome AF: 0.00211

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00199

Gnomad4 FIN exome AF: 0.000524

Gnomad4 NFE exome AF: 0.00878

Gnomad4 OTH exome AF: 0.00610

GnomAD4 genome AF: 0.00454 AC: 692 AN: 152298 Hom.: 2 Cov.: 32 AF XY: 0.00422 AC XY: 314 AN XY: 74472

Gnomad4 AFR AF: 0.00207

Gnomad4 AMR AF: 0.00555

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00722

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00616 Hom.: 1

Bravo AF: 0.00505

TwinsUK AF: 0.00620 AC: 23

ALSPAC AF: 0.00960 AC: 37

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00860 AC: 74

ExAC AF: 0.00453 AC: 550

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00635

EpiControl AF: 0.00764

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	GEMIN5: BP4, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 08, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.21
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.36	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.40
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.015	D
Polyphen		1.0	D
Vest4		0.60
MVP		0.79
MPC		0.45
ClinPred		0.024	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.35
gMVP		0.40

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: rs61749643; hg19: chr5-154278839;