1-183517758-C-T

Variant names:

• chr1-183517758-C-T
• rs1391258803
• NM_001375584.1:c.250C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001375584.1(SMG7):​c.250C>T​(p.Arg84Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,774 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SMG7 NM_001375584.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.63
• Publications: 0 publications found

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]

SMG7 Gene-Disease associations (from GenCC):

• autoimmune disease

  Inheritance: AD Classification: NO_KNOWN Submitted by: Illumina

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.776

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001375584.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMG7	NM_001375584.1	MANE Select	c.250C>T	p.Arg84Trp	missense	Exon 4 of 23	NP_001362513.1	A0A8I5KYV3
	SMG7	NM_001350220.2		c.337C>T	p.Arg113Trp	missense	Exon 6 of 25	NP_001337149.1	A0A8I5KSL3
	SMG7	NM_001394133.1		c.337C>T	p.Arg113Trp	missense	Exon 5 of 24	NP_001381062.1	A0A8I5KSL3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMG7	ENST00000688051.1	MANE Select	c.250C>T	p.Arg84Trp	missense	Exon 4 of 23	ENSP00000510175.1	A0A8I5KYV3
	SMG7	ENST00000507469.5	TSL:1	c.250C>T	p.Arg84Trp	missense	Exon 4 of 23	ENSP00000425133.1	Q92540-4
	SMG7	ENST00000347615.6	TSL:1	c.250C>T	p.Arg84Trp	missense	Exon 4 of 22	ENSP00000340766.2	Q92540-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461774 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727204

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111906

Other (OTH) AF: 0.0000166 AC: 1 AN: 60392

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.040	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		3.6
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-6.5	D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.64		Loss of disorder (P = 0.0078)
MVP		0.65
MPC		1.9
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.80
gMVP		0.67
Mutation Taster		=16/84	disease causing

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

Other links and lift over

dbSNP: rs1391258803; hg19: chr1-183486893;