rs1554066397

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM5PP2PP5_Very_Strong

The NM_000344.4(SMN1):c.5C>G(p.Ala2Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2V) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0051 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00062 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SMN1
NM_000344.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 2.76

Publications

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

SMN1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr5-70925108-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 634935.Status of the report is criteria_provided_single_submitter, 1 stars.

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.

PP5

Variant 5-70925108-C-G is Pathogenic according to our data. Variant chr5-70925108-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 9168.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000344.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SMN1	NM_000344.4	MANE Select	c.5C>G	p.Ala2Gly	missense	Exon 1 of 9	NP_000335.1	Q16637-1
SMN1	NM_001297715.1		c.5C>G	p.Ala2Gly	missense	Exon 1 of 8	NP_001284644.1	Q16637-3
SMN1	NM_022874.2		c.5C>G	p.Ala2Gly	missense	Exon 1 of 8	NP_075012.1	Q16637-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SMN1	ENST00000380707.9	TSL:1 MANE Select	c.5C>G	p.Ala2Gly	missense	Exon 1 of 9	ENSP00000370083.4	Q16637-1
SMN1	ENST00000351205.8	TSL:1	c.5C>G	p.Ala2Gly	missense	Exon 1 of 8	ENSP00000305857.5	Q16637-1
SMN1	ENST00000506163.5	TSL:1	c.5C>G	p.Ala2Gly	missense	Exon 1 of 8	ENSP00000424926.1	Q16637-3

Frequencies

GnomAD3 genomes

AF:

0.00455

AC:

AN:

1760

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00687

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00150

AC:

AN:

8024

AF XY:

0.000938

show subpopulations

Gnomad AFR exome

AF:

0.00659

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000617

AC:

AN:

42172

Hom.:

Cov.:

AF XY:

0.000404

AC XY:

AN XY:

22260

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00500

AC:

AN:

3802

American (AMR)

AF:

0.000870

AC:

AN:

2300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1840

East Asian (EAS)

AF:

0.00

AC:

AN:

1362

South Asian (SAS)

AF:

0.00

AC:

AN:

6420

European-Finnish (FIN)

AF:

0.00

AC:

AN:

1030

Middle Eastern (MID)

AF:

0.00

AC:

AN:

174

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

23064

Other (OTH)

AF:

0.00229

AC:

AN:

2180

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000000260358), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.356

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00508

AC:

AN:

1770

Hom.:

Cov.:

AF XY:

0.00775

AC XY:

AN XY:

774

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00763

AC:

AN:

1180

American (AMR)

AF:

0.00

AC:

AN:

116

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AF:

0.00

AC:

AN:

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

306

Other (OTH)

AF:

0.00

AC:

AN:

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000477346), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000674

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Kugelberg-Welander disease (2)

not provided (1)

Spinal muscular atrophy (1)

Spinal muscular atrophy, type II (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.060

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.067

Eigen

Benign

0.056

Eigen_PC

Benign

0.016

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.81

M_CAP

Pathogenic

0.83

MetaRNN

Uncertain

0.73

MetaSVM

Pathogenic

1.2

PhyloP100

2.8

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-0.87

REVEL

Uncertain

0.54

Sift

Uncertain

0.018

Sift4G

Uncertain

0.038

Vest4

0.37

MutPred

0.67

Loss of sheet (P = 0.0457)

MVP

0.98

MPC

1.4

ClinPred

0.94

GERP RS

2.9

PromoterAI

-0.12

Neutral

(source)

Varity_R

0.18

gMVP

0.51

Mutation Taster

=1/99

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over