rs187925143

chr5-70951971-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1 PM2 BP4_Strong

The NM_000344.4(SMN1):c.865T>A(p.Cys289Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000527 in 1,613,186 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C289Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 27)
  • Exomes 𝑓: 0.000051 (1 hom.)
• Consequence: SMN1 NM_000344.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.0560

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 Uncertain_significance. Variant got 0 ACMG points.

• PM1: In a chain Survival motor neuron protein (size 292) in uniprot entity SMN_HUMAN there are 52 pathogenic changes around while only 0 benign (100%) in NM_000344.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03862834).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMN1	NM_000344.4	c.865T>A	p.Cys289Ser	missense_variant	8/9	ENST00000380707.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMN1	ENST00000380707.9	c.865T>A	p.Cys289Ser	missense_variant	8/9	1	NM_000344.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152006 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000590

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000169 AC: 42 AN: 248214 Hom.: 1 AF XY: 0.000141 AC XY: 19 AN XY: 134456

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000985

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000181

Gnomad OTH exome AF: 0.000493

GnomAD4 exome AF: 0.0000506 AC: 74 AN: 1461062 Hom.: 1 Cov.: 31 AF XY: 0.0000495 AC XY: 36 AN XY: 726888

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00103

Gnomad4 ASJ exome AF: 0.000306

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000720

Gnomad4 OTH exome AF: 0.000182

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152124 Hom.: 0 Cov.: 27 AF XY: 0.000108 AC XY: 8 AN XY: 74368

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000524

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.0000901 Hom.: 0

Bravo AF: 0.000178

ExAC AF: 0.0000989 AC: 12

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 09, 2022

Variant summary: SMN1 c.865T>A (p.Cys289Ser) results in a non-conservative amino acid change located in the Survival motor neuron C-Terminal tail domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 385156 control chromosomes, predominantly at a frequency of 0.00098 within the Latino subpopulation in the gnomAD database, including 1 homozygote. This frequency is not higher than expected for a pathogenic variant in SMN1 causing Spinal Muscular Atrophy (0.0002 vs 0.0025), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.865T>A in individuals affected with Spinal Muscular Atrophy and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Werdnig-Hoffmann disease;C0152109:Kugelberg-Welander disease;C0393538:Spinal muscular atrophy, type II;C1838230:Spinal muscular atrophy, type IV Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 09, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.10
Cadd	Benign	16
Dann	Benign	0.74
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.57	T;.;T;T
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.039	T;T;T;T
MetaSVM	Uncertain	0.13	D
MutationTaster	Benign	1.0	D;N;N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.0	N;N;N;.
REVEL	Uncertain	0.35
Sift	Benign	0.33	T;T;T;.
Sift4G	Benign	0.51	T;T;T;T
Vest4		0.11
MutPred		0.42		.;Gain of methylation at K285 (P = 0.0441);.;Gain of methylation at K285 (P = 0.0441);
MVP		0.98
MPC		1.9
ClinPred		0.050	T
GERP RS		-1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.049
gMVP		0.42

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: rs187925143; hg19: chr5-70247798;