17-59210230-T-C

Position:

• chr17-59210230-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018149.7(SMG8):​c.179T>C​(p.Leu60Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,457,384 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: SMG8 NM_018149.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.62

Genes affected

SMG8 (HGNC:25551): (SMG8 nonsense mediated mRNA decay factor) Involved in nuclear-transcribed mRNA catabolic process, nonsense-mediated decay and regulation of protein kinase activity. Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000265303 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12765184).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMG8	NM_018149.7	c.179T>C	p.Leu60Pro	missense_variant	1/4	ENST00000300917.10	NP_060619.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMG8	ENST00000300917.10	c.179T>C	p.Leu60Pro	missense_variant	1/4	1	NM_018149.7	ENSP00000300917.4
ENSG00000265303	ENST00000577660.1	c.136-4575T>C		intron_variant		3		ENSP00000464167.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457384 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 724734

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: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 21, 2022

The c.179T>C (p.L60P) alteration is located in exon 1 (coding exon 1) of the SMG8 gene. This alteration results from a T to C substitution at nucleotide position 179, causing the leucine (L) at amino acid position 60 to be replaced by a proline (P). 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	0.29
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	23
DANN	Benign	0.93
DEOGEN2	Benign	0.010	T;.;T
Eigen	Benign	-0.18
Eigen_PC	Benign	0.058
FATHMM_MKL	Benign	0.50	D
LIST_S2	Benign	0.71	.;T;T
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.95	L;L;L
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	0.13	N;.;N
REVEL	Benign	0.069
Sift	Benign	0.21	T;.;T
Sift4G	Benign	0.24	T;T;T
Polyphen		0.0	B;.;B
Vest4		0.19
MutPred		0.46		Loss of helix (P = 0.0093);Loss of helix (P = 0.0093);Loss of helix (P = 0.0093);
MVP		0.28
MPC		0.52
ClinPred		0.50	T
GERP RS		5.5
Varity_R		0.68
gMVP		0.50

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-57287591;