ENST00000932553.1:c.-23C>G

Variant names:

• chr5-70925081-C-G
• rs1331455653
• ENST00000932553.1:c.-23C>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The ENST00000932553.1(SMN1):​c.-23C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.036 (4 hom., cov: 1)
  • Exomes 𝑓: 0.0097 (5 hom.)
  • Failed GnomAD Quality Control
• Consequence: SMN1 ENST00000932553.1 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0780
• Publications: 0 publications found

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: Ambry Genetics, PanelApp Australia, Genomics England PanelApp, Orphanet
• spinal muscular atrophy, type II

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
• spinal muscular atrophy, type III

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
• spinal muscular atrophy, type IV

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 5-70925081-C-G is Benign according to our data. Variant chr5-70925081-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1217482.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000932553.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMN1	NM_001297715.1		c.-23C>G		5_prime_UTR	Exon 1 of 8	NP_001284644.1	Q16637-3
	SMN1	NM_022874.2		c.-23C>G		5_prime_UTR	Exon 1 of 8	NP_075012.1	Q16637-2
	SMN1	NM_000344.4	MANE Select	c.-23C>G		upstream_gene	N/A	NP_000335.1	Q16637-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMN1	ENST00000932553.1		c.-23C>G		5_prime_UTR	Exon 1 of 9	ENSP00000602612.1
	SMN1	ENST00000932548.1		c.-23C>G		5_prime_UTR	Exon 1 of 8	ENSP00000602607.1
	SMN1	ENST00000503079.6	TSL:5	c.-23C>G		5_prime_UTR	Exon 1 of 7	ENSP00000428128.1	Q16637-2

Frequencies

GnomAD3 genomes AF: 0.0355 AC: 153 AN: 4308 Hom.: 4 Cov.: 1

Gnomad AFR AF: 0.0514

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0245

Gnomad ASJ AF: 0.00806

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00228

Gnomad OTH AF: 0.0429

GnomAD2 exomes AF: 0.0204 AC: 100 AN: 4902 AF XY: 0.0164

Gnomad AFR exome AF: 0.0791

Gnomad AMR exome AF: 0.00495

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00125

Gnomad OTH exome AF: 0.00694

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00970 AC: 290 AN: 29898 Hom.: 5 Cov.: 0 AF XY: 0.00823 AC XY: 131 AN XY: 15918

African (AFR) AF: 0.0832 AC: 252 AN: 3030

American (AMR) AF: 0.00792 AC: 13 AN: 1642

Ashkenazi Jewish (ASJ) AF: 0.00164 AC: 2 AN: 1218

East Asian (EAS) AF: 0.00 AC: 0 AN: 838

South Asian (SAS) AF: 0.000427 AC: 2 AN: 4682

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 690

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 110

European-Non Finnish (NFE) AF: 0.000372 AC: 6 AN: 16124

Other (OTH) AF: 0.00959 AC: 15 AN: 1564

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0361 AC: 156 AN: 4316 Hom.: 4 Cov.: 1 AF XY: 0.0377 AC XY: 72 AN XY: 1912

African (AFR) AF: 0.0521 AC: 143 AN: 2746

American (AMR) AF: 0.0246 AC: 7 AN: 284

Ashkenazi Jewish (ASJ) AF: 0.00806 AC: 1 AN: 124

East Asian (EAS) AF: 0.00 AC: 0 AN: 50

South Asian (SAS) AF: 0.00 AC: 0 AN: 90

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 34

European-Non Finnish (NFE) AF: 0.00229 AC: 2 AN: 874

Other (OTH) AF: 0.0441 AC: 3 AN: 68

Alfa AF: 0.0175 Hom.: 5

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	8.6
DANN	Benign	0.88
PhyloP100		0.078
PromoterAI		0.077	Neutral
Mutation Taster		=300/0	polymorphism

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

Other links and lift over

dbSNP: rs1331455653; hg19: chr5-70220908;