Genetic Variant SMUG1:p.Ser48Leu (chr12-54183798-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001351260.2(SMUG1):c.-55C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000576 in 1,614,118 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00041 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00059 ( 0 hom. )

Consequence

SMUG1
NM_001351260.2 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.56

Variant links:

Genes affected

SMUG1 (HGNC:17148): (single-strand-selective monofunctional uracil-DNA glycosylase 1) This gene encodes a protein that participates in base excision repair by removing uracil from single- and double-stranded DNA. Many alternatively spliced transcript variants exist for this gene; the full-length nature is known for some but not all of the variants. [provided by RefSeq, Aug 2011]

SMUG1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.033905864).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMUG1	NM_001243787.2 link	c.143C>T	p.Ser48Leu	missense_variant	Exon 3 of 4	ENST00000682136.1	NP_001230716.1	Q53HV7-1A0A024RAZ8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMUG1	ENST00000682136.1 link	c.143C>T	p.Ser48Leu	missense_variant	Exon 3 of 4		NM_001243787.2	ENSP00000507590.1		Q53HV7-1

Frequencies

GnomAD3 genomes

AF:

0.000407

AC:

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00113

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000617

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000585

AC:

147

AN:

251328

Hom.:

AF XY:

0.000559

AC XY:

AN XY:

135850

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000231

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000925

Gnomad NFE exome

AF:

0.000976

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000592

AC:

866

AN:

1461852

Hom.:

Cov.:

AF XY:

0.000590

AC XY:

429

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000201

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000562

Gnomad4 NFE exome

AF:

0.000696

Gnomad4 OTH exome

AF:

0.000795

GnomAD4 genome

AF:

0.000414

AC:

AN:

152266

Hom.:

Cov.:

AF XY:

0.000376

AC XY:

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.000168

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00113

Gnomad4 NFE

AF:

0.000618

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000695

Hom.:

Bravo

AF:

0.000340

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.000741

AC:

EpiCase

AF:

0.000545

EpiControl

AF:

0.000889

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.143C>T (p.S48L) alteration is located in exon 1 (coding exon 1) of the SMUG1 gene. This alteration results from a C to T substitution at nucleotide position 143, causing the serine (S) at amino acid position 48 to be replaced by a leucine (L). 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

0.094

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.37

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.25

.;T;.;.;.;T;.;T;.;T;.;.;T;T

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.65

LIST_S2

Benign

0.80

.;.;.;.;T;.;T;T;T;T;T;T;T;T

M_CAP

Benign

0.016

MetaRNN

Benign

0.034

T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Uncertain

2.8

M;M;M;M;.;M;M;M;.;.;.;.;.;.

PrimateAI

Benign

0.48

PROVEAN

Uncertain

-3.1

D;D;D;D;D;D;D;D;D;D;D;D;D;D

REVEL

Benign

0.11

Sift

Benign

0.11

T;T;T;T;T;T;T;T;T;T;T;T;T;T

Sift4G

Benign

0.13

T;T;T;T;T;T;T;T;T;.;T;.;.;T

Polyphen

0.12

B;P;B;B;D;P;B;P;.;.;.;.;.;.

Vest4

0.12

MVP

0.64

MPC

0.21

ClinPred

0.064

GERP RS

3.0

Varity_R

0.069

gMVP

0.32

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

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