12-54182204-T-G

Position:

• chr12-54182204-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001243787.2(SMUG1):​c.705A>C​(p.Glu235Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,648 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SMUG1 NM_001243787.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.896

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33122328).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMUG1	NM_001243787.2	c.705A>C	p.Glu235Asp	missense_variant	4/4	ENST00000682136.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMUG1	ENST00000682136.1	c.705A>C	p.Glu235Asp	missense_variant	4/4		NM_001243787.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459648 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 725706

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

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

Jan 23, 2024

The c.705A>C (p.E235D) alteration is located in exon 1 (coding exon 1) of the SMUG1 gene. This alteration results from a A to C substitution at nucleotide position 705, causing the glutamic acid (E) at amino acid position 235 to be replaced by an aspartic acid (D). 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	0.36
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.083	T;T;T
Eigen	Benign	0.0033
Eigen_PC	Benign	-0.023
FATHMM_MKL	Benign	0.67	D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.33	T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.9	L;L;L
MutationTaster	Benign	0.83	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Benign	0.15
Sift	Benign	0.24	T;T;T
Sift4G	Benign	0.28	T;T;T
Polyphen		0.97	D;D;D
Vest4		0.34
MutPred		0.34		Gain of catalytic residue at L237 (P = 2e-04);Gain of catalytic residue at L237 (P = 2e-04);Gain of catalytic residue at L237 (P = 2e-04);
MVP		0.75
MPC		0.82
ClinPred		0.78	D
GERP RS		1.8
Varity_R		0.11
gMVP		0.66

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-54575988;