rs104893922

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1PP2PP3_StrongPP5_Very_Strong

The NM_000344.4(SMN1):c.815A>G(p.Tyr272Cys) 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 Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 0)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SMN1
NM_000344.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 8.49

Publications

4 publications found

Variant links:

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 Gene-Disease associations (from GenCC):

spinal muscular atrophy
Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
spinal muscular atrophy, type 1
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Genomics England PanelApp
spinal muscular atrophy, type II
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
spinal muscular atrophy, type III
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
spinal muscular atrophy, type IV
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet

SMN1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 15 ACMG points.

PM1

In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000344.4

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 25 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 0.058423 (below the threshold of 3.09). Trascript score misZ: 0.12361 (below the threshold of 3.09). GenCC associations: The gene is linked to spinal muscular atrophy, type III, spinal muscular atrophy, type IV, spinal muscular atrophy, type 1, spinal muscular atrophy, spinal muscular atrophy, type II.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.993

PP5

Variant 5-70946157-A-G is Pathogenic according to our data. Variant chr5-70946157-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 9166.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMN1	NM_000344.4 link	c.815A>G	p.Tyr272Cys	missense_variant	Exon 7 of 9	ENST00000380707.9	NP_000335.1	Q16637-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMN1	ENST00000380707.9 link	c.815A>G	p.Tyr272Cys	missense_variant	Exon 7 of 9	1	NM_000344.4	ENSP00000370083.4		Q16637-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

5714

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

2992

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AF:

0.00

AC:

AN:

448

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

194

East Asian (EAS)

AF:

0.00

AC:

AN:

106

South Asian (SAS)

AF:

0.00

AC:

AN:

828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

158

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

3696

Other (OTH)

AF:

0.00

AC:

AN:

244

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Werdnig-Hoffmann disease

Pathogenic:2

Mar 01, 2016

Molecular Diagnostics Lab, Nemours Children's Health, Delaware

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 1995

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Spinal muscular atrophy

Pathogenic:1

Feb 02, 2022

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. (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from tyrosine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0501 - Missense variant is highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This is one of the most common pathogenic variants reported in patients with spinal muscular atrophy (PMID: 7813012, 10205265, 10679938, 31301241). (SP) 1208 - Inheritance information for this variant is not currently available. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided

Pathogenic:1

Jun 01, 2023

Athena Diagnostics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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)). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. Studies show this variant causes reduced self-oligomerization, and reduced binding to Sm proteins (PMID: 9590291, 10500148). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.90

.;D;D;.;D;D

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

D;.;D;D;D;D

M_CAP

Pathogenic

0.90

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

PhyloP100

8.5

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-7.4

D;D;D;D;.;.

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

D;D;D;D;.;.

Sift4G

Pathogenic

0.0010

D;D;D;D;D;D

Vest4

0.91

MutPred

0.97

.;Gain of helix (P = 0.132);.;Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);

MVP

1.0

MPC

2.1

ClinPred

1.0

GERP RS

3.4

Varity_R

0.94

gMVP

0.96

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over