chr17-59210674-A-G

Position:

• chr17-59210674-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PS1_Moderate PM2 PP3_Strong PP5

The NM_018149.7(SMG8):​c.623A>G​(p.His208Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMG8 NM_018149.7 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.25

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 Likely_pathogenic. Variant got 9 ACMG points.

• PS1: Transcript NM_018149.7 (SMG8) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.971
• PP5: Variant 17-59210674-A-G is Pathogenic according to our data. Variant chr17-59210674-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 1064668.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr17-59210674-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMG8	NM_018149.7	c.623A>G	p.His208Arg	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.623A>G	p.His208Arg	missense_variant	1/4	1	NM_018149.7	ENSP00000300917.4
ENSG00000265303	ENST00000577660.1	c.136-4131A>G		intron_variant		3		ENSP00000464167.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Alzahrani-Kuwahara syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	T;.;T
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	.;D;D
M_CAP	Benign	0.061	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Uncertain	0.017	D
MutationAssessor	Uncertain	2.9	M;M;M
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-6.8	D;.;D
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D;.;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.99	D;.;D
Vest4		0.99
MutPred		0.88		Loss of catalytic residue at L210 (P = 0.0384);Loss of catalytic residue at L210 (P = 0.0384);Loss of catalytic residue at L210 (P = 0.0384);
MVP		0.78
MPC		1.2
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.95
gMVP		0.94

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: chr17-57288035;