Variant chr17-59210694-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_018149.7(SMG8):c.643C>A(p.Pro215Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SMG8
NM_018149.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.84

Variant links:

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]

SMG8 links:

ENSG00000265303 (HGNC:):

ENSG00000265303 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.858

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMG8	NM_018149.7 linkuse as main transcript	c.643C>A	p.Pro215Thr	missense_variant	1/4	ENST00000300917.10	NP_060619.4	Q8ND04-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMG8	ENST00000300917.10 linkuse as main transcript	c.643C>A	p.Pro215Thr	missense_variant	1/4	1	NM_018149.7	ENSP00000300917.4		Q8ND04-1
ENSG00000265303	ENST00000577660.1 linkuse as main transcript	c.136-4111C>A		intron_variant		3		ENSP00000464167.1		J3QRE1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251334

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135870

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461856

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

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:

0.00

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

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 25, 2023

The c.643C>A (p.P215T) alteration is located in exon 1 (coding exon 1) of the SMG8 gene. This alteration results from a C to A substitution at nucleotide position 643, causing the proline (P) at amino acid position 215 to be replaced by a threonine (T). 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

Pathogenic

0.98

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

0.11

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.20

T;.;T

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

.;D;D

M_CAP

Benign

0.045

MetaRNN

Pathogenic

0.86

D;D;D

MetaSVM

Benign

-0.58

MutationAssessor

Benign

1.7

L;L;L

PrimateAI

Pathogenic

0.82

PROVEAN

Uncertain

-3.9

D;.;D

REVEL

Uncertain

0.57

Sift

Uncertain

0.0030

D;.;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;.;D

Vest4

0.91

MutPred

0.68

Gain of catalytic residue at P215 (P = 0.0185);Gain of catalytic residue at P215 (P = 0.0185);Gain of catalytic residue at P215 (P = 0.0185);

MVP

0.62

MPC

1.1

ClinPred

0.96

GERP RS

5.7

Varity_R

0.85

gMVP

0.76

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