5-70925090-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_000344.4(SMN1):c.-14C>T 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 Benign (★).

• Frequency:
  • Genomes: 𝑓 0.50 (510 hom., cov: 1)
  • Exomes 𝑓: 0.076 (825 hom.)
  • Failed GnomAD Quality Control
• Consequence: SMN1 NM_000344.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.685

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BS2: High Homozygotes in GnomAdExome at 271 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMN1	NM_000344.4	c.-14C>T		5_prime_UTR_variant	1/9	ENST00000380707.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMN1	ENST00000380707.9	c.-14C>T		5_prime_UTR_variant	1/9	1	NM_000344.4	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 1248 AN: 2502 Hom.: 501 Cov.: 1 FAILED QC

Gnomad AFR AF: 0.838

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.305

Gnomad ASJ AF: 0.212

Gnomad EAS AF: 0.0238

Gnomad SAS AF: 0.0595

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0226

Gnomad OTH AF: 0.263

GnomAD3 exomes AF: 0.153 AC: 903 AN: 5906 Hom.: 271 AF XY: 0.119 AC XY: 379 AN XY: 3182

Gnomad AFR exome AF: 0.723

Gnomad AMR exome AF: 0.0586

Gnomad ASJ exome AF: 0.0931

Gnomad EAS exome AF: 0.00638

Gnomad SAS exome AF: 0.00680

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0139

Gnomad OTH exome AF: 0.0562

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0763 AC: 2673 AN: 35014 Hom.: 825 Cov.: 0 AF XY: 0.0637 AC XY: 1188 AN XY: 18662

Gnomad4 AFR exome AF: 0.739

Gnomad4 AMR exome AF: 0.0760

Gnomad4 ASJ exome AF: 0.0927

Gnomad4 EAS exome AF: 0.00664

Gnomad4 SAS exome AF: 0.0142

Gnomad4 FIN exome AF: 0.00116

Gnomad4 NFE exome AF: 0.00891

Gnomad4 OTH exome AF: 0.108

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.505 AC: 1267 AN: 2510 Hom.: 510 Cov.: 1 AF XY: 0.504 AC XY: 550 AN XY: 1092

Gnomad4 AFR AF: 0.840

Gnomad4 AMR AF: 0.309

Gnomad4 ASJ AF: 0.212

Gnomad4 EAS AF: 0.0238

Gnomad4 SAS AF: 0.0625

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0227

Gnomad4 OTH AF: 0.278

Alfa AF: 0.131 Hom.: 522

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 09, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	4.3
Dann	Benign	0.96

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: rs867507129; hg19: chr5-70220917;