5-70941458-G-A

Position:

• chr5-70941458-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1 BP4_Moderate

The NM_000344.4(SMN1):​c.223G>A​(p.Ala75Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 0)
• Consequence: SMN1 NM_000344.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.448

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 27 pathogenic changes around while only 0 benign (100%) in NM_000344.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.14968967).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMN1	NM_000344.4	c.223G>A	p.Ala75Thr	missense_variant	3/9	ENST00000380707.9	NP_000335.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMN1	ENST00000380707.9	c.223G>A	p.Ala75Thr	missense_variant	3/9	1	NM_000344.4	ENSP00000370083.4

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Sep 07, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Uncertain	0.013	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	14
DANN	Benign	0.82
DEOGEN2	Benign	0.35	.;T;T;.;T;T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.79	T;.;T;T;T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.15	T;T;T;T;T;T
MetaSVM	Uncertain	0.24	D
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.47	N;N;N;N;.;N
REVEL	Benign	0.11
Sift	Benign	0.57	T;T;T;T;.;T
Sift4G	Benign	0.59	T;T;T;T;T;T
Vest4		0.094
MutPred		0.33		Gain of phosphorylation at A75 (P = 0.0022);Gain of phosphorylation at A75 (P = 0.0022);Gain of phosphorylation at A75 (P = 0.0022);Gain of phosphorylation at A75 (P = 0.0022);Gain of phosphorylation at A75 (P = 0.0022);Gain of phosphorylation at A75 (P = 0.0022);
MVP		0.98
MPC		0.80
ClinPred		0.21	T
GERP RS		1.7
Varity_R		0.036
gMVP		0.30

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-70237285;