17-2299731-T-G

Variant names:

• chr17-2299731-T-G
• rs1885987
• NM_017575.5:c.1022A>C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_017575.5(SMG6):​c.1022A>C​(p.Asn341Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.348 in 1,613,934 control chromosomes in the GnomAD database, including 103,675 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.29 (7740 hom., cov: 32)
  • Exomes 𝑓: 0.35 (95935 hom.)
• Consequence: SMG6 NM_017575.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.37

Genes affected

SMG6 (HGNC:17809): (SMG6 nonsense mediated mRNA decay factor) This gene encodes a component of the telomerase ribonucleoprotein complex responsible for the replication and maintenance of chromosome ends. The encoded protein also plays a role in the nonsense-mediated mRNA decay (NMD) pathway, providing the endonuclease activity near the premature translation termination codon that is needed to initiate NMD. Alternatively spliced transcript variants encoding distinct protein isoforms have been described. [provided by RefSeq, Feb 2014]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002092868).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.372 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMG6	NM_017575.5	c.1022A>C	p.Asn341Thr	missense_variant	Exon 2 of 19	ENST00000263073.11	NP_060045.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMG6	ENST00000263073.11	c.1022A>C	p.Asn341Thr	missense_variant	Exon 2 of 19	1	NM_017575.5	ENSP00000263073.5

Frequencies

GnomAD3 genomes AF: 0.288 AC: 43713 AN: 151942 Hom.: 7734 Cov.: 32

Gnomad AFR AF: 0.0893

Gnomad AMI AF: 0.385

Gnomad AMR AF: 0.373

Gnomad ASJ AF: 0.426

Gnomad EAS AF: 0.168

Gnomad SAS AF: 0.241

Gnomad FIN AF: 0.393

Gnomad MID AF: 0.331

Gnomad NFE AF: 0.376

Gnomad OTH AF: 0.325

GnomAD3 exomes AF: 0.336 AC: 84443 AN: 251484 Hom.: 15715 AF XY: 0.334 AC XY: 45419 AN XY: 135916

Gnomad AFR exome AF: 0.0816

Gnomad AMR exome AF: 0.446

Gnomad ASJ exome AF: 0.441

Gnomad EAS exome AF: 0.164

Gnomad SAS exome AF: 0.233

Gnomad FIN exome AF: 0.396

Gnomad NFE exome AF: 0.372

Gnomad OTH exome AF: 0.357

GnomAD4 exome AF: 0.355 AC: 518359 AN: 1461874 Hom.: 95935 Cov.: 70 AF XY: 0.351 AC XY: 255232 AN XY: 727236

Gnomad4 AFR exome AF: 0.0764

Gnomad4 AMR exome AF: 0.439

Gnomad4 ASJ exome AF: 0.433

Gnomad4 EAS exome AF: 0.158

Gnomad4 SAS exome AF: 0.234

Gnomad4 FIN exome AF: 0.399

Gnomad4 NFE exome AF: 0.372

Gnomad4 OTH exome AF: 0.346

GnomAD4 genome AF: 0.288 AC: 43737 AN: 152060 Hom.: 7740 Cov.: 32 AF XY: 0.287 AC XY: 21363 AN XY: 74334

Gnomad4 AFR AF: 0.0895

Gnomad4 AMR AF: 0.373

Gnomad4 ASJ AF: 0.426

Gnomad4 EAS AF: 0.168

Gnomad4 SAS AF: 0.242

Gnomad4 FIN AF: 0.393

Gnomad4 NFE AF: 0.376

Gnomad4 OTH AF: 0.324

Alfa AF: 0.357 Hom.: 25096

Bravo AF: 0.279

ESP6500AA AF: 0.0940 AC: 414

ESP6500EA AF: 0.387 AC: 3325

ExAC AF: 0.325 AC: 39502

Asia WGS AF: 0.238 AC: 830 AN: 3478

EpiCase AF: 0.380

EpiControl AF: 0.381

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	14
DANN	Benign	0.94
DEOGEN2	Benign	0.033	T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.41
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.62	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.0	N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.87	N
REVEL	Benign	0.11
Sift	Benign	0.13	T
Sift4G	Benign	0.21	T
Polyphen		0.0010	B
Vest4		0.073
MPC		0.17
ClinPred		0.0068	T
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.047
gMVP		0.068

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

Other links and lift over

dbSNP: rs1885987; hg19: chr17-2203025; COSMIC: COSV53967360; COSMIC: COSV53967360;