rs1554066659

Positions:

• chr5-70946127-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM5 PP3_Strong PP5_Very_Strong

The NM_000344.4(SMN1):​c.785G>T​(p.Ser262Ile) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S262G) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 0)
• Consequence: SMN1 NM_000344.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.19

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 16 ACMG points.

• PM1: In a region_of_interest Involved in homooligomerization (size 28) in uniprot entity SMN_HUMAN there are 24 pathogenic changes around while only 0 benign (100%) in NM_000344.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-70946126-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 9178.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.975
• PP5: Variant 5-70946127-G-T is Pathogenic according to our data. Variant chr5-70946127-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 9165.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-70946127-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMN1	NM_000344.4	c.785G>T	p.Ser262Ile	missense_variant	7/9	ENST00000380707.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMN1	ENST00000380707.9	c.785G>T	p.Ser262Ile	missense_variant	7/9	1	NM_000344.4	P1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Kugelberg-Welander disease Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	Mar 03, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 19, 2020	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0104 - Dominant Negative is a mechanism of disease for this gene. (N) 0106 - Variant is heterozygous. (N) 0200 - Variant is predicted to result in a missense amino acid change from serine to leucine (exon 7). (N) 0251 - Variant is heterozygous. (N) 0301 – Population information is not available for this region in gnomAD. (N) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0600 - Variant is located in an annotated domain or motif (SMN domain; NCBI, Decipher, PDB). (N) 0704 - Comparable variant has low previous evidence for pathogenicity. At least one alternative change in the same residue resulting in a glycine has been reported in a patient with type III spinal muscular atrophy (ClinVar; PMID: 23022347). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times in patients with type III spinal muscular atrophy (ClinVar; PMID: 9158159; PMID: 23073312; PMID: 9199562). (P) 0905 - No segregation evidence has been identified for this variant. (N) 1002 - Moderate functional evidence supporting abnormal protein function. In vitro studies show that this variant reduces RNA binding efficiency and impacts self-oligomerisation (PMID: 9668169; PMID: 23022347). (P) 1206 - Variant is paternally inherited. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 1997	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Athena Diagnostics

Sep 07, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	31
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.88	.;D;D;.;D;D
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.96	D;.;D;D;D;D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	A;A;A;A;A
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-5.5	D;D;D;D;.;.
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D;D;D;.;.
Sift4G	Uncertain	0.0030	D;D;D;D;D;D
Vest4		0.84
MutPred		0.83		.;Loss of disorder (P = 0.0245);.;Loss of disorder (P = 0.0245);Loss of disorder (P = 0.0245);Loss of disorder (P = 0.0245);
MVP		0.98
MPC		2.0
ClinPred		1.0	D
GERP RS		3.4
Varity_R		0.92
gMVP		0.89

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: rs1554066659; hg19: chr5-70241954;