NM_017575.5:c.1022A>C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 52 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017575.5. 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
	SMG6	NM_017575.5	MANE Select	c.1022A>C	p.Asn341Thr	missense	Exon 2 of 19	NP_060045.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMG6	ENST00000263073.11	TSL:1 MANE Select	c.1022A>C	p.Asn341Thr	missense	Exon 2 of 19	ENSP00000263073.5	Q86US8-1
	SMG6	ENST00000883972.1		c.1022A>C	p.Asn341Thr	missense	Exon 2 of 18	ENSP00000554031.1

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

GnomAD2 exomes AF: 0.336 AC: 84443 AN: 251484 AF XY: 0.334

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 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

African (AFR) AF: 0.0764 AC: 2559 AN: 33480

American (AMR) AF: 0.439 AC: 19612 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.433 AC: 11319 AN: 26136

East Asian (EAS) AF: 0.158 AC: 6292 AN: 39700

South Asian (SAS) AF: 0.234 AC: 20152 AN: 86258

European-Finnish (FIN) AF: 0.399 AC: 21301 AN: 53420

Middle Eastern (MID) AF: 0.363 AC: 2095 AN: 5768

European-Non Finnish (NFE) AF: 0.372 AC: 414111 AN: 1111992

Other (OTH) AF: 0.346 AC: 20918 AN: 60396

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

African (AFR) AF: 0.0895 AC: 3717 AN: 41534

American (AMR) AF: 0.373 AC: 5686 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.426 AC: 1477 AN: 3470

East Asian (EAS) AF: 0.168 AC: 870 AN: 5174

South Asian (SAS) AF: 0.242 AC: 1166 AN: 4814

European-Finnish (FIN) AF: 0.393 AC: 4152 AN: 10560

Middle Eastern (MID) AF: 0.332 AC: 97 AN: 292

European-Non Finnish (NFE) AF: 0.376 AC: 25537 AN: 67946

Other (OTH) AF: 0.324 AC: 684 AN: 2112

Alfa AF: 0.345 Hom.: 32781

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 v4.9

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
PhyloP100		3.4
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
Mutation Taster		=98/2	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: rs1885987; hg19: chr17-2203025; COSMIC: COSV53967360; COSMIC: COSV53967360;