rs4916

Variant names:

• chr5-70076526-T-C
• rs4916
• NM_017411.4:c.840T>C

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BP7

The NM_017411.4(SMN2):​c.840T>C​(p.Phe280Phe) variant causes a synonymous 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 0.00013 (0 hom., cov: 19)
  • Exomes 𝑓: 0.000073 (15 hom.)
  • Failed GnomAD Quality Control
• Consequence: SMN2 NM_017411.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.459
• Publications: 96 publications found

Genes affected

SMN2 (HGNC:11118): (survival of motor neuron 2, centromeric) 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. While mutations in the telomeric copy are associated with spinal muscular atrophy, mutations in this gene, the centromeric copy, do not lead to disease. This gene 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 full length 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. Four transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Sep 2008]

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 5-70076526-T-C is Benign according to our data. Variant chr5-70076526-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 3388533.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.459 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMN2	NM_017411.4	c.840T>C	p.Phe280Phe	synonymous_variant	Exon 8 of 9	ENST00000380743.9	NP_059107.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMN2	ENST00000380743.9	c.840T>C	p.Phe280Phe	synonymous_variant	Exon 8 of 9	1	NM_017411.4	ENSP00000370119.4

Frequencies

GnomAD3 genomes AF: 0.000131 AC: 17 AN: 129458 Hom.: 0 Cov.: 19

Gnomad AFR AF: 0.000426

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000782

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000486

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000441 AC: 10 AN: 226852 AF XY: 0.0000405

Gnomad AFR exome AF: 0.0000803

Gnomad AMR exome AF: 0.0000951

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000589

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000727 AC: 97 AN: 1334670 Hom.: 15 Cov.: 29 AF XY: 0.0000631 AC XY: 42 AN XY: 665344

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000539 AC: 14 AN: 25990

American (AMR) AF: 0.0000739 AC: 3 AN: 40596

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23470

East Asian (EAS) AF: 0.000615 AC: 23 AN: 37384

South Asian (SAS) AF: 0.0000739 AC: 6 AN: 81150

European-Finnish (FIN) AF: 0.000141 AC: 7 AN: 49500

Middle Eastern (MID) AF: 0.000742 AC: 4 AN: 5392

European-Non Finnish (NFE) AF: 0.0000344 AC: 35 AN: 1016084

Other (OTH) AF: 0.0000907 AC: 5 AN: 55104

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000131 AC: 17 AN: 129542 Hom.: 0 Cov.: 19 AF XY: 0.0000794 AC XY: 5 AN XY: 62934

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000425 AC: 13 AN: 30584

American (AMR) AF: 0.0000782 AC: 1 AN: 12792

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3108

East Asian (EAS) AF: 0.00 AC: 0 AN: 4782

South Asian (SAS) AF: 0.00 AC: 0 AN: 4246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9338

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 278

European-Non Finnish (NFE) AF: 0.0000486 AC: 3 AN: 61718

Other (OTH) AF: 0.00 AC: 0 AN: 1814

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000843 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SMN2: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	14
DANN	Benign	0.83
PhyloP100		0.46
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs4916; hg19: chr5-69372353;