rs104893927

Variant names:

• chr5-70942367-G-C
• rs104893927
• NM_000344.4:c.283G>C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PP3_Strong PP5_Very_Strong

The NM_000344.4(SMN1):​c.283G>C​(p.Gly95Arg) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 0)
• Consequence: SMN1 NM_000344.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.12

Genes affected

SMN1 (HGNC:11117): (survival of motor neuron 1, telomeric) This gene is part of a 500 kb inverted duplication on chromosome 5q13. This duplicated region contains at least four genes and repetitive elements which make it prone to rearrangements and deletions. The repetitiveness and complexity of the sequence have also caused difficulty in determining the organization of this genomic region. The telomeric and centromeric copies of this gene are nearly identical and encode the same protein. However, mutations in this gene, the telomeric copy, are associated with spinal muscular atrophy; mutations in the centromeric copy do not lead to disease. The centromeric copy may be a modifier of disease caused by mutation in the telomeric copy. The critical sequence difference between the two genes is a single nucleotide in exon 7, which is thought to be an exon splice enhancer. Note that the nine exons of both the telomeric and centromeric copies are designated historically as exon 1, 2a, 2b, and 3-8. It is thought that gene conversion events may involve the two genes, leading to varying copy numbers of each gene. The protein encoded by this gene localizes to both the cytoplasm and the nucleus. Within the nucleus, the protein localizes to subnuclear bodies called gems which are found near coiled bodies containing high concentrations of small ribonucleoproteins (snRNPs). This protein forms heteromeric complexes with proteins such as SIP1 and GEMIN4, and also interacts with several proteins known to be involved in the biogenesis of snRNPs, such as hnRNP U protein and the small nucleolar RNA binding protein. Multiple transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Jul 2014]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a domain Tudor (size 60) in uniprot entity SMN_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_000344.4
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 5-70942367-G-C is Pathogenic according to our data. Variant chr5-70942367-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 9176.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-70942367-G-C is described in UniProt as null. Variant chr5-70942367-G-C is described in UniProt as null. Variant chr5-70942367-G-C is described in UniProt as null. Variant chr5-70942367-G-C is described in UniProt as null. Variant chr5-70942367-G-C is described in UniProt as null. Variant chr5-70942367-G-C is described in UniProt as null. Variant chr5-70942367-G-C is described in UniProt as null. Variant chr5-70942367-G-C is described in UniProt as null. Variant chr5-70942367-G-C is described in Lovd as [Pathogenic]. Variant chr5-70942367-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMN1	NM_000344.4	c.283G>C	p.Gly95Arg	missense_variant	Exon 4 of 9	ENST00000380707.9	NP_000335.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMN1	ENST00000380707.9	c.283G>C	p.Gly95Arg	missense_variant	Exon 4 of 9	1	NM_000344.4	ENSP00000370083.4

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spinal muscular atrophy Pathogenic:1

Jul 17, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with spinal muscular atrophy-1 (MIM#253300), spinal muscular atrophy-2 (MIM#253550), spinal muscular atrophy-3 (MIM#253400) and spinal muscular atrophy-4 (MIM#271150). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to arginine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). However, the sequencing coverage in this region is very poor in gnomAD. (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated Tudor domain (PMID: 15580564). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. It has been reported as pathogenic by a clinical testing laboratory (ClinVar). It has also been reported in three unrelated individuals with spinal muscular atrophy who either has only one copy of SMN2 gene or are compound heterozygous with a deletion in SMN1 gene (PMIDs: 15580564, 31903607, 33481221), and an individual with probable diagnosis of spinal muscular atrophy who is also heterozygous for loss of SMN1 exon 7 (PMID: 32721234). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. In vitro experiments showed SMN protein with this variant had reduced binding to spliceosomal proteins, Sm-B and Sm-D1, as well as FUS/TLS and TDP-43 proteins which are associated with motor neuron disease (PMIDs: 15580564, 23255347). (SP) 1205 - This variant has been shown to be maternally inherited (LABID). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Kugelberg-Welander disease Pathogenic:1

Jan 01, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Mar 18, 2016

Molecular Diagnostics Lab, Nemours Children's Health, Delaware

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.92	.;D;.;D;D
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;.;D;D;D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-6.5	D;D;D;.;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D;D;.;D
Sift4G	Uncertain	0.0020	D;D;D;D;D
Vest4		0.93
MutPred		0.93		Gain of solvent accessibility (P = 2e-04);Gain of solvent accessibility (P = 2e-04);Gain of solvent accessibility (P = 2e-04);Gain of solvent accessibility (P = 2e-04);Gain of solvent accessibility (P = 2e-04);
MVP		0.98
MPC		2.1
ClinPred		1.0	D
GERP RS		3.5
Varity_R		0.94
gMVP		0.78

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: rs104893927; hg19: chr5-70238194;