rs1554066397

chr5-70925108-C-Gchr5-70925108-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM5 PP5_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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 2.76

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 12 ACMG points.

• PM1: In a modified_residue N-acetylalanine (size 0) in uniprot entity SMN_HUMAN there are 4 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 ClinVar as [Likely_pathogenic]. Clinvar id is 634935.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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	UniProt
SMN1	NM_000344.4	c.5C>G	p.Ala2Gly	missense_variant	1/9	ENST00000380707.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMN1	ENST00000380707.9	c.5C>G	p.Ala2Gly	missense_variant	1/9	1	NM_000344.4	P1

Frequencies

GnomAD3 genomes AF: 0.00455 AC: 8 AN: 1760 Hom.: 0 Cov.: 0

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: 26 AN: 42172 Hom.: 0 Cov.: 0 AF XY: 0.000404 AC XY: 9 AN XY: 22260

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: 9 AN: 1770 Hom.: 0 Cov.: 0 AF XY: 0.00775 AC XY: 6 AN XY: 774

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.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Kugelberg-Welander disease Pathogenic:2

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

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	D
BayesDel_noAF	Uncertain	0.060
Cadd	Uncertain	25
Dann	Uncertain	0.99
Eigen	Benign	0.056
Eigen_PC	Benign	0.016
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.81	T;.;T;T;T;T
M_CAP	Pathogenic	0.83	D
MetaRNN	Uncertain	0.73	D;D;D;D;D;D
MetaSVM	Pathogenic	1.2	D
MutationTaster	Benign	0.083	A;A;A;A;A
PrimateAI	Uncertain	0.78	T
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	D
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

Other links and lift over

dbSNP: rs1554066397; hg19: chr5-70220935;