rs142507451

Positions:

chr16-67660141-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001082486.2(ACD):c.80G>A(p.Arg27Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00268 in 1,612,532 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. R27R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0017 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0028 ( 26 hom. )

Consequence

ACD
NM_001082486.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.296

Variant links:

Genes affected

ACD (HGNC:25070): (ACD shelterin complex subunit and telomerase recruitment factor) This gene encodes a protein that is involved in telomere function. This protein is one of six core proteins in the telosome/shelterin telomeric complex, which functions to maintain telomere length and to protect telomere ends. Through its interaction with other components, this protein plays a key role in the assembly and stabilization of this complex, and it mediates the access of telomerase to the telomere. Multiple transcript variants encoding different isoforms have been found for this gene. This gene, which is also referred to as TPP1, is distinct from the unrelated TPP1 gene on chromosome 11, which encodes tripeptidyl-peptidase I. [provided by RefSeq, Jul 2008]

ACD links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003171146).

BP6

Variant 16-67660141-C-T is Benign according to our data. Variant chr16-67660141-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 475768.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-67660141-C-T is described in Lovd as [Benign]. Variant chr16-67660141-C-T is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAdExome4 at 26 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ACD	NM_001082486.2 linkuse as main transcript	c.80G>A	p.Arg27Gln	missense_variant	1/12	ENST00000620761.6
ACD	NM_022914.3 linkuse as main transcript	c.80G>A	p.Arg27Gln	missense_variant	1/12
ACD	NM_001410884.1 linkuse as main transcript	c.80G>A	p.Arg27Gln	missense_variant	1/11
ACD	XR_429728.4 linkuse as main transcript	n.120G>A		non_coding_transcript_exon_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACD	ENST00000620761.6 linkuse as main transcript	c.80G>A	p.Arg27Gln	missense_variant	1/12	1	NM_001082486.2	P1	Q96AP0-3

Frequencies

GnomAD3 genomes

AF:

0.00167

AC:

254

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00109

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0122

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00197

Gnomad OTH

AF:

0.00430

GnomAD3 exomes

AF:

0.00251

AC:

606

AN:

241284

Hom.:

AF XY:

0.00291

AC XY:

384

AN XY:

132070

show subpopulations

Gnomad AFR exome

AF:

0.000808

Gnomad AMR exome

AF:

0.000698

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000167

Gnomad SAS exome

AF:

0.0105

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00222

Gnomad OTH exome

AF:

0.00136

GnomAD4 exome

AF:

0.00279

AC:

4075

AN:

1460236

Hom.:

Cov.:

AF XY:

0.00303

AC XY:

2203

AN XY:

726404

show subpopulations

Gnomad4 AFR exome

AF:

0.000687

Gnomad4 AMR exome

AF:

0.000671

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0104

Gnomad4 FIN exome

AF:

0.000269

Gnomad4 NFE exome

AF:

0.00267

Gnomad4 OTH exome

AF:

0.00212

GnomAD4 genome

AF:

0.00167

AC:

254

AN:

152296

Hom.:

Cov.:

AF XY:

0.00167

AC XY:

124

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.00108

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.0122

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.00197

Gnomad4 OTH

AF:

0.00426

Alfa

AF:

0.00223

Hom.:

Bravo

AF:

0.00136

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00389

AC:

ESP6500AA

AF:

0.000684

AC:

ESP6500EA

AF:

0.00163

AC:

ExAC

AF:

0.00242

AC:

293

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.00251

EpiControl

AF:

0.00184

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	ACD: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 14, 2018	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Dyskeratosis congenita, autosomal dominant 6

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 21, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.72

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.25

.;T;T;T;T;.

Eigen

Benign

-0.90

Eigen_PC

Benign

-0.95

FATHMM_MKL

Benign

0.034

LIST_S2

Benign

0.79

T;T;.;T;T;.

MetaRNN

Benign

0.0032

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

.;L;.;.;.;L

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.31

REVEL

Benign

0.059

Sift4G

Benign

0.39

.;T;T;.;T;.

Polyphen

0.48, 0.43

.;P;.;.;.;B

Vest4

0.066, 0.071, 0.10

MVP

0.29

MPC

0.17

ClinPred

0.011

GERP RS

-1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.12

gMVP

0.15

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

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