NM_017575.5:c.4220G>A

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_017575.5(SMG6):c.4220G>A(p.Arg1407Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000419 in 1,574,948 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000039 ( 0 hom. )

Consequence

SMG6
NM_017575.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.74

Variant links:

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]

SMG6 links:

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]

HIC1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.18356195).

BS2

High AC in GnomAd4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMG6	NM_017575.5 link	c.4220G>A	p.Arg1407Gln	missense_variant	Exon 19 of 19	ENST00000263073.11	NP_060045.4	Q86US8-1
HIC1	NM_006497.4 link	c.*2697C>T		3_prime_UTR_variant	Exon 2 of 2	ENST00000619757.5	NP_006488.2	Q14526-2A0PJI1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMG6	ENST00000263073.11 link	c.4220G>A	p.Arg1407Gln	missense_variant	Exon 19 of 19	1	NM_017575.5	ENSP00000263073.5		Q86US8-1
HIC1	ENST00000619757.5 link	c.*2697C>T		3_prime_UTR_variant	Exon 2 of 2	1	NM_006497.4	ENSP00000477858.1		Q14526-2

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

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

GnomAD3 exomes

AF:

0.0000489

AC:

AN:

184024

Hom.:

AF XY:

0.0000203

AC XY:

AN XY:

98724

show subpopulations

Gnomad AFR exome

AF:

0.000826

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS 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:

0.0000387

AC:

AN:

1422630

Hom.:

Cov.:

AF XY:

0.0000327

AC XY:

AN XY:

704130

show subpopulations

Gnomad4 AFR exome

AF:

0.000460

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000123

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000339

Gnomad4 OTH exome

AF:

0.0000340

GnomAD4 genome

AF:

0.0000722

AC:

AN:

152318

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.000265

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.000219

ESP6500AA

AF:

0.000683

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000334

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 22, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4220G>A (p.R1407Q) alteration is located in exon 19 (coding exon 19) of the SMG6 gene. This alteration results from a G to A substitution at nucleotide position 4220, causing the arginine (R) at amino acid position 1407 to be replaced by a glutamine (Q). 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

Uncertain

0.48

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.17

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.17

T;.;.

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.96

D;.;D

M_CAP

Benign

0.019

MetaRNN

Benign

0.18

T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Uncertain

2.4

M;.;.

PrimateAI

Uncertain

0.72

PROVEAN

Uncertain

-2.5

N;.;D

REVEL

Benign

0.28

Sift

Uncertain

0.011

D;.;D

Sift4G

Uncertain

0.038

D;T;T

Polyphen

1.0

D;.;.

Vest4

0.61

MVP

0.53

MPC

0.73

ClinPred

0.28

GERP RS

5.0

Varity_R

0.78

gMVP

0.73

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over