1-183529400-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001375584.1(SMG7):c.710G>A(p.Arg237Gln) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000684 in 1,609,334 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000065 (0 hom.)
• Consequence: SMG7 NM_001375584.1 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.12

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15410757).
• BS2: High AC in GnomAd at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMG7	NM_001375584.1	c.710G>A	p.Arg237Gln	missense_variant, splice_region_variant	8/23	ENST00000688051.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMG7	ENST00000688051.1	c.710G>A	p.Arg237Gln	missense_variant, splice_region_variant	8/23		NM_001375584.1	P4

Frequencies

GnomAD3 genomes AF: 0.0000987 AC: 15 AN: 152008 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000474

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000154 AC: 38 AN: 246934 Hom.: 0 AF XY: 0.000172 AC XY: 23 AN XY: 133396

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000771

Gnomad SAS exome AF: 0.0000340

Gnomad FIN exome AF: 0.000418

Gnomad NFE exome AF: 0.0000981

Gnomad OTH exome AF: 0.000499

GnomAD4 exome AF: 0.0000652 AC: 95 AN: 1457326 Hom.: 0 Cov.: 31 AF XY: 0.0000552 AC XY: 40 AN XY: 724832

Gnomad4 AFR exome AF: 0.0000301

Gnomad4 AMR exome AF: 0.0000229

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000543

Gnomad4 NFE exome AF: 0.0000477

Gnomad4 OTH exome AF: 0.0000498

GnomAD4 genome AF: 0.0000987 AC: 15 AN: 152008 Hom.: 0 Cov.: 32 AF XY: 0.0000808 AC XY: 6 AN XY: 74218

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000192

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000474

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000587 Hom.: 0

Bravo AF: 0.0000604

ExAC AF: 0.000140 AC: 17

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 03, 2023

The c.710G>A (p.R237Q) alteration is located in exon 8 (coding exon 8) of the SMG7 gene. This alteration results from a G to A substitution at nucleotide position 710, causing the arginine (R) at amino acid position 237 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.11
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D
M_CAP	Benign	0.0086	T
MetaRNN	Benign	0.15	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-1.6	N;N;N;N;N;N
REVEL	Benign	0.21
Sift	Uncertain	0.013	D;D;D;D;D;D
Sift4G	Benign	0.073	T;T;T;T;D;T
Polyphen		0.77	P;.;.;P;.;P
Vest4		0.64
MutPred		0.41		Gain of ubiquitination at K261 (P = 0.0527);.;.;.;.;.;
MVP		0.77
MPC		2.0
ClinPred		0.16	T
GERP RS		4.9
Varity_R		0.27
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs200930565; hg19: chr1-183498535; COSMIC: COSV100750144; COSMIC: COSV100750144;