5-70925108-C-G

Position:

chr5-70925108-C-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM5PP5_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 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:4

Conservation

PhyloP100: 2.76

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM1

In a chain Survival motor neuron protein (size 292) in uniprot entity SMN_HUMAN there are 27 pathogenic changes around while only 0 benign (100%) in NM_000344.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr5-70925108-C-T is described in Lovd as [Pathogenic].

PP5

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMN1	NM_000344.4 link	c.5C>G	p.Ala2Gly	missense_variant	1/9	ENST00000380707.9	NP_000335.1	Q16637-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMN1	ENST00000380707.9 link	c.5C>G	p.Ala2Gly	missense_variant	1/9	1	NM_000344.4	ENSP00000370083.4		Q16637-1

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

GnomAD4 exome

AF:

0.000617

AC:

AN:

42172

Hom.:

Cov.:

AF XY:

0.000404

AC XY:

AN XY:

22260

show subpopulations

Gnomad4 AFR exome

AF:

0.00500

Gnomad4 AMR exome

AF:

0.000870

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00229

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

Gnomad4 AFR

AF:

0.00763

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000674

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Kugelberg-Welander disease

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 1998	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	Feb 26, 2016	- -

Spinal muscular atrophy, type II

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 1998

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Athena Diagnostics

Sep 21, 2022

Frequency data for this variant in the Genome Aggregation Database (gnomAD) 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 individuals with SMA types II, III, or IV who also carried a heterozygous pathogenic deletion of exon 7 in the SMN1 gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 12515823) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.060

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.067

.;T;T;.;T;T

Eigen

Benign

0.056

Eigen_PC

Benign

0.016

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.81

T;.;T;T;T;T

M_CAP

Pathogenic

0.83

MetaRNN

Uncertain

0.73

D;D;D;D;D;D

MetaSVM

Pathogenic

1.2

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-0.87

N;N;N;N;.;N

REVEL

Uncertain

0.54

Sift

Uncertain

0.018

D;D;D;D;.;D

Sift4G

Uncertain

0.038

D;D;T;D;D;D

Vest4

0.37

MutPred

0.67

Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);

MVP

0.98

MPC

1.4

ClinPred

0.94

GERP RS

2.9

Varity_R

0.18

gMVP

0.51

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over