chr17-2065554-G-A

Position:

• chr17-2065554-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_017575.5(SMG6):​c.3961C>T​(p.Arg1321Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000041 in 1,461,726 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: SMG6 NM_017575.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.78

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 Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMG6	NM_017575.5	c.3961C>T	p.Arg1321Trp	missense_variant	17/19	ENST00000263073.11	NP_060045.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMG6	ENST00000263073.11	c.3961C>T	p.Arg1321Trp	missense_variant	17/19	1	NM_017575.5	ENSP00000263073	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461726 Hom.: 0 Cov.: 33 AF XY: 0.00000550 AC XY: 4 AN XY: 727164

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 02, 2023

The c.3961C>T (p.R1321W) alteration is located in exon 17 (coding exon 17) of the SMG6 gene. This alteration results from a C to T substitution at nucleotide position 3961, causing the arginine (R) at amino acid position 1321 to be replaced by a tryptophan (W). 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	0.94
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.25	T;.;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.95	D;.;D
M_CAP	Benign	0.036	D
MetaRNN	Uncertain	0.72	D;D;D
MetaSVM	Benign	-0.83	T
MutationAssessor	Pathogenic	3.0	M;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-4.2	D;.;D
REVEL	Uncertain	0.30
Sift	Uncertain	0.0040	D;.;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.83
MutPred		0.42		Loss of disorder (P = 0);.;.;
MVP		0.57
MPC		0.70
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.53
gMVP		0.78

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: chr17-1968848; COSMIC: COSV104547578; COSMIC: COSV104547578;