chr1-183512864-G-T

Variant names:

• chr1-183512864-G-T
• rs185963873
• NM_001375584.1:c.57G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PVS1_Supporting PM2

The NM_001394140.1(SMG7):​c.3G>T​(p.Met1?) variant causes a start lost change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000718 in 139,342 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000072 (0 hom., cov: 28)
  • Exomes 𝑓: 7.6e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SMG7 NM_001394140.1 start_lost
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.10
• Publications: 2 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.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 25 codons. Genomic position: 183515939. Lost 0.022 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001394140.1. 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.57G>T	p.Met19Ile	missense	Exon 2 of 23	NP_001362513.1	A0A8I5KYV3
	SMG7	NM_001394140.1		c.3G>T	p.Met1?	start_lost	Exon 3 of 23	NP_001381069.1
	SMG7	NM_001394145.1		c.3G>T	p.Met1?	start_lost	Exon 5 of 25	NP_001381074.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMG7	ENST00000688051.1	MANE Select	c.57G>T	p.Met19Ile	missense	Exon 2 of 23	ENSP00000510175.1	A0A8I5KYV3
	SMG7	ENST00000507469.5	TSL:1	c.57G>T	p.Met19Ile	missense	Exon 2 of 23	ENSP00000425133.1	Q92540-4
	SMG7	ENST00000347615.6	TSL:1	c.57G>T	p.Met19Ile	missense	Exon 2 of 22	ENSP00000340766.2	Q92540-1

Frequencies

GnomAD3 genomes AF: 0.00000718 AC: 1 AN: 139280 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000152

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000434 AC: 1 AN: 230288 AF XY: 0.00000801

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000952

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 7.62e-7 AC: 1 AN: 1312662 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 656046

African (AFR) AF: 0.00 AC: 0 AN: 29860

American (AMR) AF: 0.00 AC: 0 AN: 39978

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24056

East Asian (EAS) AF: 0.00 AC: 0 AN: 35828

South Asian (SAS) AF: 0.00 AC: 0 AN: 77208

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51200

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4580

European-Non Finnish (NFE) AF: 0.00000100 AC: 1 AN: 995806

Other (OTH) AF: 0.00 AC: 0 AN: 54146

GnomAD4 genome AF: 0.00000718 AC: 1 AN: 139342 Hom.: 0 Cov.: 28 AF XY: 0.0000151 AC XY: 1 AN XY: 66410

African (AFR) AF: 0.00 AC: 0 AN: 38142

American (AMR) AF: 0.00 AC: 0 AN: 13032

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3392

East Asian (EAS) AF: 0.00 AC: 0 AN: 4532

South Asian (SAS) AF: 0.00 AC: 0 AN: 4302

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7312

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 256

European-Non Finnish (NFE) AF: 0.0000152 AC: 1 AN: 65628

Other (OTH) AF: 0.00 AC: 0 AN: 1862

ExAC AF: 0.00000824 AC: 1

Asia WGS AF: 0.000289 AC: 1 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.013	T
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L
PhyloP100		9.1
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.33	N
REVEL	Benign	0.26
Sift	Uncertain	0.015	D
Sift4G	Benign	0.39	T
Polyphen		0.025	B
Vest4		0.63
MutPred		0.39		Loss of catalytic residue at M48 (P = 0.0094)
MVP		0.56
MPC		1.0
ClinPred		0.60	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22
gMVP		0.69
Mutation Taster		=225/75	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs185963873; hg19: chr1-183481999;