chr5-70951942-G-T

Variant names:

• chr5-70951942-G-T
• rs76163360
• NM_000344.4:c.836G>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5

The NM_000344.4(SMN1):​c.836G>T​(p.Gly279Val) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G279R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 27)
• Consequence: SMN1 NM_000344.4 missense, splice_region
• Scores: Splicing: ADA: 0.8227
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.42
• Publications: 3 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, Orphanet, Genomics England PanelApp
• 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: Pathogenic. The variant received 12 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000344.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-70951941-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1929368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 25 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 0.058423 (below the threshold of 3.09). Trascript score misZ: 0.12361 (below the threshold of 3.09). GenCC associations: The gene is linked to spinal muscular atrophy, type III, spinal muscular atrophy, type IV, spinal muscular atrophy, type 1, spinal muscular atrophy, spinal muscular atrophy, type II.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 5-70951942-G-T is Pathogenic according to our data. Variant chr5-70951942-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 9167.Status of the report is no_assertion_criteria_provided, 0 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMN1	NM_000344.4	MANE Select	c.836G>T	p.Gly279Val	missense splice_region	Exon 8 of 9	NP_000335.1
	SMN1	NM_022874.2		c.740G>T	p.Gly247Val	missense splice_region	Exon 7 of 8	NP_075012.1
	SMN1	NM_001297715.1		c.835-497G>T		intron	N/A	NP_001284644.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMN1	ENST00000380707.9	TSL:1 MANE Select	c.836G>T	p.Gly279Val	missense splice_region	Exon 8 of 9	ENSP00000370083.4
	SMN1	ENST00000351205.8	TSL:1	c.836G>T	p.Gly279Val	missense splice_region	Exon 8 of 8	ENSP00000305857.5
	SMN1	ENST00000506163.5	TSL:1	c.835-497G>T		intron	N/A	ENSP00000424926.1

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 27

Alfa AF: 0.0000539 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Werdnig-Hoffmann disease Pathogenic:1

May 01, 1997

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.77	T
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
PhyloP100		4.4
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-6.8	D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Vest4		0.81
MutPred		0.96		Gain of sheet (P = 0.0149)
MVP		0.99
MPC		2.1
ClinPred		0.99	D
GERP RS		4.2
Varity_R		0.87
gMVP		0.86
Mutation Taster		=35/65	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.82
dbscSNV1_RF	Benign	0.65
Splicevardb		2.0
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: rs76163360; hg19: chr5-70247769;