Variant chr16-18859071-T-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_015092.5(SMG1):c.4064A>T(p.Tyr1355Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000725 in 1,379,662 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000072 ( 0 hom. )

Consequence

SMG1
NM_015092.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.79

Variant links:

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]

SMG1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMG1	NM_015092.5 linkuse as main transcript	c.4064A>T	p.Tyr1355Phe	missense_variant	28/63	ENST00000446231.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMG1	ENST00000446231.7 linkuse as main transcript	c.4064A>T	p.Tyr1355Phe	missense_variant	28/63	1	NM_015092.5	P1	Q96Q15-1
SMG1	ENST00000565324.5 linkuse as main transcript	c.3734A>T	p.Tyr1245Phe	missense_variant	26/61	1
SMG1	ENST00000563235.5 linkuse as main transcript	c.2357A>T	p.Tyr786Phe	missense_variant	16/17	2
SMG1	ENST00000569764.1 linkuse as main transcript	n.1454A>T		non_coding_transcript_exon_variant	2/2	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000151

AC:

AN:

66422

Hom.:

AF XY:

0.00

AC XY:

AN XY:

33136

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000338

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000725

AC:

AN:

1379662

Hom.:

Cov.:

AF XY:

0.00000734

AC XY:

AN XY:

681360

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000837

Gnomad4 OTH exome

AF:

0.0000173

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 02, 2021

The c.4064A>T (p.Y1355F) alteration is located in exon 28 (coding exon 28) of the SMG1 gene. This alteration results from a A to T substitution at nucleotide position 4064, causing the tyrosine (Y) at amino acid position 1355 to be replaced by a phenylalanine (F). 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

Uncertain

0.021

BayesDel_noAF

Benign

-0.21

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.051

T;T

Eigen

Benign

0.095

Eigen_PC

Benign

0.20

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

D;D

M_CAP

Benign

0.031

MetaRNN

Uncertain

0.50

T;T

MetaSVM

Benign

-0.82

MutationAssessor

Benign

0.63

N;.

MutationTaster

Benign

0.95

D;D;D

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-1.4

N;.

REVEL

Benign

0.24

Sift

Benign

0.25

T;.

Polyphen

0.60

P;.

Vest4

0.39

MutPred

0.52

Gain of disorder (P = 0.172);.;

MVP

0.57

MPC

0.33

ClinPred

0.89

GERP RS

4.4

Varity_R

0.22

gMVP

0.31

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over