rs397514517

chr5-70942473-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM5 PP3_Strong PP5

The NM_000344.4(SMN1):c.389A>G(p.Tyr130Cys) 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 Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y130H) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 0)
• Consequence: SMN1 NM_000344.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.50

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a region_of_interest Required for interaction with RPP20/POP7 (size 112) in uniprot entity SMN_HUMAN there are 13 pathogenic changes around while only 0 benign (100%) in NM_000344.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-70942472-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 39513.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 5-70942473-A-G is Pathogenic according to our data. Variant chr5-70942473-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 39512.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMN1	NM_000344.4	c.389A>G	p.Tyr130Cys	missense_variant	4/9	ENST00000380707.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMN1	ENST00000380707.9	c.389A>G	p.Tyr130Cys	missense_variant	4/9	1	NM_000344.4	P1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Kugelberg-Welander disease Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 21, 2012

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
Cadd	Pathogenic	30
Dann	Uncertain	1.0
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D;.;D;D;D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	0.94	D
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-7.2	D;D;D;.;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D;D;.;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Vest4		0.95
MutPred		0.97		Loss of disorder (P = 0.1482);Loss of disorder (P = 0.1482);Loss of disorder (P = 0.1482);Loss of disorder (P = 0.1482);Loss of disorder (P = 0.1482);
MVP		0.99
MPC		2.0
ClinPred		1.0	D
GERP RS		3.5
Varity_R		0.95
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs397514517; hg19: chr5-70238300;