17-2065554-G-A

Variant names:

• chr17-2065554-G-A
• NM_017575.5:c.3961C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

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. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. 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
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

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.3961C>T	p.Arg1321Trp	missense	Exon 17 of 19	NP_060045.4
	SMG6	NM_001256827.2		c.1237C>T	p.Arg413Trp	missense	Exon 10 of 12	NP_001243756.1	Q86US8-3
	SMG6	NM_001256828.1		c.1237C>T	p.Arg413Trp	missense	Exon 9 of 11	NP_001243757.1	Q86US8-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMG6	ENST00000263073.11	TSL:1 MANE Select	c.3961C>T	p.Arg1321Trp	missense	Exon 17 of 19	ENSP00000263073.5	Q86US8-1
	SMG6	ENST00000354901.8	TSL:1	c.1237C>T	p.Arg413Trp	missense	Exon 10 of 12	ENSP00000346977.4	Q86US8-3
	SMG6	ENST00000573166.5	TSL:1	n.2291C>T		non_coding_transcript_exon	Exon 5 of 7

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53344

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5724

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111996

Other (OTH) AF: 0.00 AC: 0 AN: 60390

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000000000318634), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.036	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Benign	-0.83	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		3.8
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-4.2	D
REVEL	Uncertain	0.30
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0030	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
Mutation Taster		=56/44	polymorphism

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

hg19: chr17-1968848; COSMIC: COSV104547578; COSMIC: COSV104547578;