16-18850274-C-T

Position:

• chr16-18850274-C-T

Variant summary

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

The NM_015092.5(SMG1):​c.5246G>A​(p.Ser1749Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000822 in 1,460,470 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: SMG1 NM_015092.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.94

Genes affected

SMG1 (HGNC:30045): (SMG1 nonsense mediated mRNA decay associated PI3K related kinase) This gene encodes a protein involved in nonsense-mediated mRNA decay (NMD) as part of the mRNA surveillance complex. The protein has kinase activity and is thought to function in NMD by phosphorylating the regulator of nonsense transcripts 1 protein. Alternatively spliced transcript variants have been described, but their full-length nature has yet to be determined. [provided by RefSeq, Mar 2013]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13709539).
• BS2: High AC in GnomAdExome4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMG1	NM_015092.5	c.5246G>A	p.Ser1749Asn	missense_variant	34/63	ENST00000446231.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMG1	ENST00000446231.7	c.5246G>A	p.Ser1749Asn	missense_variant	34/63	1	NM_015092.5	P1
SMG1	ENST00000565324.5	c.4916G>A	p.Ser1639Asn	missense_variant	32/61	1
SMG1	ENST00000563448.1	n.88G>A		non_coding_transcript_exon_variant	1/10	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000822 AC: 12 AN: 1460470 Hom.: 0 Cov.: 33 AF XY: 0.00000964 AC XY: 7 AN XY: 726388

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000990

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Aug 09, 2021

The c.5246G>A (p.S1749N) alteration is located in exon 34 (coding exon 34) of the SMG1 gene. This alteration results from a G to A substitution at nucleotide position 5246, causing the serine (S) at amino acid position 1749 to be replaced by an asparagine (N). 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	Benign	0.12
BayesDel_addAF	Benign	-0.098	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	22
DANN	Benign	0.86
DEOGEN2	Benign	0.018	T;T
Eigen	Benign	-0.10
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	-0.46	N;.
MutationTaster	Benign	0.87	D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	0.22	N;.
REVEL	Benign	0.11
Sift	Benign	0.71	T;.
Polyphen		0.12	B;.
Vest4		0.58
MutPred		0.40		Loss of helix (P = 0.0444);.;
MVP		0.33
MPC		0.28
ClinPred		0.60	D
GERP RS		5.9
Varity_R		0.25
gMVP		0.15

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-18861596;