rs104893933

Positions:

• chr5-70942430-A-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PP3 PP5_Very_Strong

The NM_000344.4(SMN1):​c.346A>T​(p.Ile116Phe) variant causes a missense change involving the alteration of a non-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: -0.749

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]

SMN1 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 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, 0.823
• PP5: Variant 5-70942430-A-T is Pathogenic according to our data. Variant chr5-70942430-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 9179.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-70942430-A-T is described in UniProt as null. Variant chr5-70942430-A-T is described in UniProt as null. Variant chr5-70942430-A-T is described in UniProt as null. Variant chr5-70942430-A-T is described in UniProt as null. Variant chr5-70942430-A-T is described in UniProt as null. Variant chr5-70942430-A-T is described in UniProt as null. Variant chr5-70942430-A-T is described in UniProt as null. Variant chr5-70942430-A-T is described in UniProt as null. Variant chr5-70942430-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMN1	NM_000344.4	c.346A>T	p.Ile116Phe	missense_variant	4/9	ENST00000380707.9	NP_000335.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMN1	ENST00000380707.9	c.346A>T	p.Ile116Phe	missense_variant	4/9	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

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 14, 2021	Frequency data for this variant in the general population cannot be distinguished from that of the SMN2 gene, and is therefore uninformative in assessment of variant pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). Assessment of experimental evidence suggests this variant results in abnormal protein function. Studies indicate this variant leads to defective Sm core assembly (PMID: 16301532, 29982416). In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. The variant is located in a region that is considered important for protein function and/or structure. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 27, 2023	- -

Werdnig-Hoffmann disease Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 15, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	2.8
DANN	Benign	0.91
DEOGEN2	Pathogenic	0.81	.;D;.;D;D
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.066	N
LIST_S2	Uncertain	0.86	D;.;D;D;D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.82	D;D;D;D;D
MetaSVM	Pathogenic	0.85	D
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-3.3	D;D;D;.;D
REVEL	Uncertain	0.52
Sift	Uncertain	0.027	D;D;D;.;D
Sift4G	Benign	0.096	T;T;T;T;T
Vest4		0.41
MutPred		0.83		Gain of catalytic residue at I116 (P = 0.0087);Gain of catalytic residue at I116 (P = 0.0087);Gain of catalytic residue at I116 (P = 0.0087);Gain of catalytic residue at I116 (P = 0.0087);Gain of catalytic residue at I116 (P = 0.0087);
MVP		0.95
MPC		2.1
ClinPred		0.30	T
GERP RS		-6.9
Varity_R		0.53
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.23		Position offset: 12

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

Publications

LitVar

Other links and lift over

dbSNP: rs104893933; hg19: chr5-70238257;