rs2298083

Positions:

• chr1-183546293-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001375584.1(SMG7):​c.2698G>A​(p.Val900Ile) variant causes a missense change. The variant allele was found at a frequency of 0.126 in 1,613,736 control chromosomes in the GnomAD database, including 14,048 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.16 (2260 hom., cov: 32)
  • Exomes 𝑓: 0.12 (11788 hom.)
• Consequence: SMG7 NM_001375584.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.61

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013405085).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.263 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMG7	NM_001375584.1	c.2698G>A	p.Val900Ile	missense_variant	17/23	ENST00000688051.1	NP_001362513.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMG7	ENST00000688051.1	c.2698G>A	p.Val900Ile	missense_variant	17/23		NM_001375584.1	ENSP00000510175.1

Frequencies

GnomAD3 genomes AF: 0.160 AC: 24398 AN: 152034 Hom.: 2258 Cov.: 32

Gnomad AFR AF: 0.267

Gnomad AMI AF: 0.122

Gnomad AMR AF: 0.177

Gnomad ASJ AF: 0.0807

Gnomad EAS AF: 0.111

Gnomad SAS AF: 0.100

Gnomad FIN AF: 0.111

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.113

Gnomad OTH AF: 0.141

GnomAD3 exomes AF: 0.125 AC: 31244 AN: 250716 Hom.: 2263 AF XY: 0.118 AC XY: 16030 AN XY: 135470

Gnomad AFR exome AF: 0.267

Gnomad AMR exome AF: 0.172

Gnomad ASJ exome AF: 0.0738

Gnomad EAS exome AF: 0.105

Gnomad SAS exome AF: 0.0984

Gnomad FIN exome AF: 0.108

Gnomad NFE exome AF: 0.109

Gnomad OTH exome AF: 0.103

GnomAD4 exome AF: 0.122 AC: 178877 AN: 1461582 Hom.: 11788 Cov.: 33 AF XY: 0.121 AC XY: 87655 AN XY: 727108

Gnomad4 AFR exome AF: 0.268

Gnomad4 AMR exome AF: 0.179

Gnomad4 ASJ exome AF: 0.0741

Gnomad4 EAS exome AF: 0.101

Gnomad4 SAS exome AF: 0.102

Gnomad4 FIN exome AF: 0.108

Gnomad4 NFE exome AF: 0.120

Gnomad4 OTH exome AF: 0.123

GnomAD4 genome AF: 0.161 AC: 24424 AN: 152154 Hom.: 2260 Cov.: 32 AF XY: 0.159 AC XY: 11816 AN XY: 74392

Gnomad4 AFR AF: 0.267

Gnomad4 AMR AF: 0.177

Gnomad4 ASJ AF: 0.0807

Gnomad4 EAS AF: 0.111

Gnomad4 SAS AF: 0.101

Gnomad4 FIN AF: 0.111

Gnomad4 NFE AF: 0.113

Gnomad4 OTH AF: 0.140

Alfa AF: 0.118 Hom.: 2756

Bravo AF: 0.170

TwinsUK AF: 0.128 AC: 476

ALSPAC AF: 0.133 AC: 514

ESP6500AA AF: 0.256 AC: 1128

ESP6500EA AF: 0.110 AC: 942

ExAC AF: 0.123 AC: 14932

Asia WGS AF: 0.0990 AC: 343 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0063	.;.;T;.;.
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D;D;D;D;D
MetaRNN	Benign	0.0013	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	.;.;L;.;.
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.20	N;N;N;N;N
REVEL	Benign	0.16
Sift	Benign	0.067	T;T;T;T;D
Sift4G	Benign	0.36	T;T;T;T;T
Polyphen		0.12	B;.;B;.;B
Vest4		0.086
MPC		0.11
ClinPred		0.023	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.046
gMVP		0.16

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: rs2298083; hg19: chr1-183515428;