rs6503905

Variant names:

• chr17-59210093-A-G
• rs6503905
• NM_018149.7:c.42A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_018149.7(SMG8):​c.42A>G​(p.Ala14Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.642 in 1,577,986 control chromosomes in the GnomAD database, including 329,630 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.70 (38597 hom., cov: 31)
  • Exomes 𝑓: 0.64 (291033 hom.)
• Consequence: SMG8 NM_018149.7 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.521
• Publications: 38 publications found

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 Gene-Disease associations (from GenCC):

• Alzahrani-Kuwahara syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, ClinGen, Labcorp Genetics (formerly Invitae), PanelApp Australia

ENSG00000265303 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP7: Synonymous conserved (PhyloP=-0.521 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.89 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018149.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMG8	NM_018149.7	MANE Select	c.42A>G	p.Ala14Ala	synonymous	Exon 1 of 4	NP_060619.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMG8	ENST00000300917.10	TSL:1 MANE Select	c.42A>G	p.Ala14Ala	synonymous	Exon 1 of 4	ENSP00000300917.4	Q8ND04-1
	ENSG00000265303	ENST00000577660.1	TSL:3	c.136-4712A>G		intron	N/A	ENSP00000464167.1	J3QRE1
	SMG8	ENST00000543872.6	TSL:5	c.42A>G	p.Ala14Ala	synonymous	Exon 2 of 5	ENSP00000438748.2	Q8ND04-1

Frequencies

GnomAD3 genomes AF: 0.701 AC: 106446 AN: 151914 Hom.: 38536 Cov.: 31

Gnomad AFR AF: 0.898

Gnomad AMI AF: 0.550

Gnomad AMR AF: 0.612

Gnomad ASJ AF: 0.668

Gnomad EAS AF: 0.452

Gnomad SAS AF: 0.624

Gnomad FIN AF: 0.615

Gnomad MID AF: 0.655

Gnomad NFE AF: 0.643

Gnomad OTH AF: 0.677

GnomAD2 exomes AF: 0.619 AC: 135223 AN: 218524 AF XY: 0.617

Gnomad AFR exome AF: 0.904

Gnomad AMR exome AF: 0.529

Gnomad ASJ exome AF: 0.645

Gnomad EAS exome AF: 0.458

Gnomad FIN exome AF: 0.617

Gnomad NFE exome AF: 0.630

Gnomad OTH exome AF: 0.618

GnomAD4 exome AF: 0.636 AC: 906221 AN: 1425954 Hom.: 291033 Cov.: 54 AF XY: 0.635 AC XY: 449042 AN XY: 707344

African (AFR) AF: 0.911 AC: 29097 AN: 31950

American (AMR) AF: 0.542 AC: 20633 AN: 38034

Ashkenazi Jewish (ASJ) AF: 0.658 AC: 15474 AN: 23506

East Asian (EAS) AF: 0.446 AC: 17568 AN: 39414

South Asian (SAS) AF: 0.615 AC: 49615 AN: 80704

European-Finnish (FIN) AF: 0.620 AC: 31649 AN: 51040

Middle Eastern (MID) AF: 0.661 AC: 3672 AN: 5554

European-Non Finnish (NFE) AF: 0.639 AC: 700535 AN: 1096984

Other (OTH) AF: 0.646 AC: 37978 AN: 58768

GnomAD4 genome AF: 0.701 AC: 106561 AN: 152032 Hom.: 38597 Cov.: 31 AF XY: 0.696 AC XY: 51690 AN XY: 74294

African (AFR) AF: 0.898 AC: 37270 AN: 41504

American (AMR) AF: 0.611 AC: 9323 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.668 AC: 2316 AN: 3468

East Asian (EAS) AF: 0.452 AC: 2328 AN: 5152

South Asian (SAS) AF: 0.624 AC: 3001 AN: 4810

European-Finnish (FIN) AF: 0.615 AC: 6496 AN: 10562

Middle Eastern (MID) AF: 0.670 AC: 197 AN: 294

European-Non Finnish (NFE) AF: 0.643 AC: 43693 AN: 67960

Other (OTH) AF: 0.680 AC: 1435 AN: 2110

Alfa AF: 0.661 Hom.: 105862

Bravo AF: 0.706

Asia WGS AF: 0.577 AC: 2008 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	7.8
DANN	Benign	0.48
PhyloP100		-0.52
PromoterAI		0.19	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6503905; hg19: chr17-57287454; COSMIC: COSV56283976; COSMIC: COSV56283976;