NM_015465.5:c.3046C>G

Variant names:

• chr5-154899279-G-C
• rs61749643
• NM_015465.5:c.3046C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2 PM5 BP4

The NM_015465.5(GEMIN5):​c.3046C>G​(p.Arg1016Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign 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. R1016C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GEMIN5 NM_015465.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.14
• Publications: 12 publications found

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]

GEMIN5 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with cerebellar atrophy and motor dysfunction

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-154899279-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 562188.
• BP4: Computational evidence support a benign effect (MetaRNN=0.41540128).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GEMIN5	NM_015465.5	c.3046C>G	p.Arg1016Gly	missense_variant	Exon 22 of 28	ENST00000285873.8	NP_056280.2
GEMIN5	NM_001252156.2	c.3043C>G	p.Arg1015Gly	missense_variant	Exon 22 of 28		NP_001239085.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GEMIN5	ENST00000285873.8	c.3046C>G	p.Arg1016Gly	missense_variant	Exon 22 of 28	1	NM_015465.5	ENSP00000285873.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.00043	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.020	T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.42	T
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	1.1	L
PhyloP100		6.1
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.17
Sift	Benign	0.091	T
Sift4G	Benign	0.11	T
Polyphen		0.86	P
Vest4		0.56
MutPred		0.37		Loss of stability (P = 0.0316);
MVP		0.75
MPC		0.35
ClinPred		0.77	D
GERP RS		4.7
Varity_R		0.42
gMVP		0.41
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs61749643; hg19: chr5-154278839;