NM_000344.4:c.81+45C>T

Variant names:

• chr5-70925229-C-T
• rs1455982550
• NM_000344.4:c.81+45C>T

Variant summary

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

The NM_000344.4(SMN1):​c.81+45C>T variant causes a intron 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 Benign (★).

• Frequency:
  • Genomes: 𝑓 0.79 (5 hom., cov: 0)
  • Exomes 𝑓: 0.081 (481 hom.)
  • Failed GnomAD Quality Control
• Consequence: SMN1 NM_000344.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.377
• 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=-0.89).
• BP6: Variant 5-70925229-C-T is Benign according to our data. Variant chr5-70925229-C-T is described in ClinVar as Benign. ClinVar VariationId is 1279988.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000344.4. 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_000344.4	MANE Select	c.81+45C>T		intron	N/A	NP_000335.1	Q16637-1
	SMN1	NM_001297715.1		c.81+45C>T		intron	N/A	NP_001284644.1	Q16637-3
	SMN1	NM_022874.2		c.81+45C>T		intron	N/A	NP_075012.1	Q16637-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMN1	ENST00000380707.9	TSL:1 MANE Select	c.81+45C>T		intron	N/A	ENSP00000370083.4	Q16637-1
	SMN1	ENST00000351205.8	TSL:1	c.81+45C>T		intron	N/A	ENSP00000305857.5	Q16637-1
	SMN1	ENST00000506163.5	TSL:1	c.81+45C>T		intron	N/A	ENSP00000424926.1	Q16637-3

Frequencies

GnomAD3 genomes AF: 0.750 AC: 9 AN: 12 Hom.: 4 Cov.: 0

Gnomad AFR AF: 0.900

Gnomad EAS AF: 0.00

GnomAD2 exomes AF: 0.146 AC: 543 AN: 3728 AF XY: 0.108

Gnomad AFR exome AF: 0.730

Gnomad AMR exome AF: 0.0620

Gnomad ASJ exome AF: 0.0854

Gnomad EAS exome AF: 0.00345

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0162

Gnomad OTH exome AF: 0.0603

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0810 AC: 1624 AN: 20038 Hom.: 481 Cov.: 0 AF XY: 0.0672 AC XY: 715 AN XY: 10638

African (AFR) AF: 0.732 AC: 1247 AN: 1704

American (AMR) AF: 0.0459 AC: 83 AN: 1808

Ashkenazi Jewish (ASJ) AF: 0.104 AC: 70 AN: 672

East Asian (EAS) AF: 0.00236 AC: 2 AN: 846

South Asian (SAS) AF: 0.00976 AC: 32 AN: 3278

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 340

Middle Eastern (MID) AF: 0.121 AC: 8 AN: 66

European-Non Finnish (NFE) AF: 0.00953 AC: 100 AN: 10496

Other (OTH) AF: 0.0990 AC: 82 AN: 828

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.786 AC: 11 AN: 14 Hom.: 5 Cov.: 0 AF XY: 0.800 AC XY: 8 AN XY: 10

African (AFR) AF: 0.917 AC: 11 AN: 12

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.00 AC: 0 AN: 2

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

Alfa AF: 0.163 Hom.: 818

ClinVar

ClinVar submissions

Significance: 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	-0.89
CADD	Benign	7.0
DANN	Benign	0.80
PhyloP100		-0.38
PromoterAI		-0.061	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs1455982550; hg19: chr5-70221056;