1-183542215-G-A

Variant names:

• chr1-183542215-G-A
• rs148593325
• NM_001375584.1:c.1555G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001375584.1(SMG7):​c.1555G>A​(p.Gly519Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G519E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMG7 NM_001375584.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.21

Genes affected

SMG7 (HGNC:16792): (SMG7 nonsense mediated mRNA decay factor) This gene encodes a protein that is essential for nonsense-mediated mRNA decay (NMD); a process whereby transcripts with premature termination codons are targeted for rapid degradation by a mRNA decay complex. The mRNA decay complex consists, in part, of this protein along with proteins SMG5 and UPF1. The N-terminal domain of this protein is thought to mediate its association with SMG5 or UPF1 while the C-terminal domain interacts with the mRNA decay complex. This protein may therefore couple changes in UPF1 phosphorylation state to the degradation of NMD-candidate transcripts. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Aug 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35616443).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMG7	NM_001375584.1	c.1555G>A	p.Gly519Arg	missense_variant	Exon 14 of 23	ENST00000688051.1	NP_001362513.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMG7	ENST00000688051.1	c.1555G>A	p.Gly519Arg	missense_variant	Exon 14 of 23		NM_001375584.1	ENSP00000510175.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.023	.;.;T;T;.;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.36	T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.6	.;.;.;L;L;L
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.2	N;N;N;N;N;N
REVEL	Uncertain	0.31
Sift	Uncertain	0.0010	D;D;D;D;D;D
Sift4G	Benign	0.12	T;T;T;T;D;T
Polyphen		1.0	D;.;.;D;.;D
Vest4		0.56
MutPred		0.46		Loss of ubiquitination at K553 (P = 0.0435);.;.;.;.;.;
MVP		0.60
MPC		0.66
ClinPred		0.91	D
GERP RS		5.4
Varity_R		0.19
gMVP		0.48

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: rs148593325; hg19: chr1-183511350; COSMIC: COSV61630859;