chr17-2061521-C-T

Variant names:

• chr17-2061521-C-T
• rs376525214
• NM_017575.5:c.4231G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_017575.5(SMG6):​c.4231G>A​(p.Ala1411Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,014 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. A1411P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SMG6 NM_017575.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.92
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07982978).

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.4231G>A	p.Ala1411Thr	missense	Exon 19 of 19	NP_060045.4
	HIC1	NM_006497.4	MANE Select	c.*2686C>T		3_prime_UTR	Exon 2 of 2	NP_006488.2	Q14526-2
	SMG6	NM_001256827.2		c.1507G>A	p.Ala503Thr	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.4231G>A	p.Ala1411Thr	missense	Exon 19 of 19	ENSP00000263073.5	Q86US8-1
	SMG6	ENST00000354901.8	TSL:1	c.1507G>A	p.Ala503Thr	missense	Exon 12 of 12	ENSP00000346977.4	Q86US8-3
	HIC1	ENST00000619757.5	TSL:1 MANE Select	c.*2686C>T		3_prime_UTR	Exon 2 of 2	ENSP00000477858.1	Q14526-2

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152014 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 184590 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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 Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1422528 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 704138

African (AFR) AF: 0.00 AC: 0 AN: 32654

American (AMR) AF: 0.00 AC: 0 AN: 39442

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25436

East Asian (EAS) AF: 0.00 AC: 0 AN: 37504

South Asian (SAS) AF: 0.00 AC: 0 AN: 81260

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49550

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5602

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1092236

Other (OTH) AF: 0.00 AC: 0 AN: 58844

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152014 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 74250

African (AFR) AF: 0.0000242 AC: 1 AN: 41364

American (AMR) AF: 0.00 AC: 0 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.00 AC: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.033	T
Eigen	Benign	-0.086
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.0020	T
MetaRNN	Benign	0.080	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PhyloP100		2.9
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.39	N
REVEL	Benign	0.054
Sift	Benign	0.57	T
Sift4G	Benign	0.16	T
Polyphen		0.0090	B
Vest4		0.039
MVP		0.24
MPC		0.16
ClinPred		0.73	D
GERP RS		5.5
Varity_R		0.21
gMVP		0.20

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: rs376525214; hg19: chr17-1964815;