17-2061601-C-T

Variant names:

• chr17-2061601-C-T
• rs867472768
• NM_017575.5:c.4151G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_017575.5(SMG6):​c.4151G>A​(p.Arg1384Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000564 in 1,419,594 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000056 (0 hom.)
• Consequence: SMG6 NM_017575.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.44
• 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]

HIC1 (HGNC:4909): (HIC ZBTB transcriptional repressor 1) This gene functions as a growth regulatory and tumor repressor gene. Hypermethylation or deletion of the region of this gene have been associated with tumors and the contiguous-gene syndrome, Miller-Dieker syndrome. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Sep 2010]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 8 AD gene.

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.4151G>A	p.Arg1384Gln	missense	Exon 19 of 19	NP_060045.4
	HIC1	NM_006497.4	MANE Select	c.*2766C>T		3_prime_UTR	Exon 2 of 2	NP_006488.2	Q14526-2
	SMG6	NM_001256827.2		c.1427G>A	p.Arg476Gln	missense	Exon 12 of 12	NP_001243756.1	Q86US8-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMG6	ENST00000263073.11	TSL:1 MANE Select	c.4151G>A	p.Arg1384Gln	missense	Exon 19 of 19	ENSP00000263073.5	Q86US8-1
	SMG6	ENST00000354901.8	TSL:1	c.1427G>A	p.Arg476Gln	missense	Exon 12 of 12	ENSP00000346977.4	Q86US8-3
	HIC1	ENST00000619757.5	TSL:1 MANE Select	c.*2766C>T		3_prime_UTR	Exon 2 of 2	ENSP00000477858.1	Q14526-2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000548 AC: 1 AN: 182572 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000359

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000564 AC: 8 AN: 1419594 Hom.: 0 Cov.: 34 AF XY: 0.00000285 AC XY: 2 AN XY: 702394

African (AFR) AF: 0.00 AC: 0 AN: 32330

American (AMR) AF: 0.0000258 AC: 1 AN: 38778

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25420

East Asian (EAS) AF: 0.00 AC: 0 AN: 37058

South Asian (SAS) AF: 0.00 AC: 0 AN: 80992

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50226

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5720

European-Non Finnish (NFE) AF: 0.00000642 AC: 7 AN: 1090336

Other (OTH) AF: 0.00 AC: 0 AN: 58734

GnomAD4 genome Cov.: 34

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	0.98
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.12	T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.036	D
MetaRNN	Uncertain	0.54	D
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		7.4
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.34
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.013	D
Polyphen		1.0	D
Vest4		0.52
MutPred		0.47		Gain of sheet (P = 0.1208)
MVP		0.63
MPC		0.74
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.85
gMVP		0.77
Mutation Taster		=57/43	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

dbSNP: rs867472768; hg19: chr17-1964895; COSMIC: COSV99557986; COSMIC: COSV99557986;