rs142507451

chr16-67660141-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

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. 11/17 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.296

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]

ACMG classification

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 GnomAdExome at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACD	NM_001082486.2	c.80G>A	p.Arg27Gln	missense_variant	1/12	ENST00000620761.6
ACD	NM_022914.3	c.80G>A	p.Arg27Gln	missense_variant	1/12
ACD	NM_001410884.1	c.80G>A	p.Arg27Gln	missense_variant	1/11
ACD	XR_429728.4	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	c.80G>A	p.Arg27Gln	missense_variant	1/12	1	NM_001082486.2	P1

Frequencies

GnomAD3 genomes AF: 0.00167 AC: 254 AN: 152178 Hom.: 0 Cov.: 33

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.: 3 AF XY: 0.00291 AC XY: 384 AN XY: 132070

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.: 26 Cov.: 34 AF XY: 0.00303 AC XY: 2203 AN XY: 726404

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.: 0 Cov.: 33 AF XY: 0.00167 AC XY: 124 AN XY: 74460

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.: 2

Bravo AF: 0.00136

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.000684 AC: 3

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.00242 AC: 293

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.00251

EpiControl AF: 0.00184

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
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	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	ACD: BP4, BS1, BS2 -
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	-	- -

Dyskeratosis congenita, autosomal dominant 6 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	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	T
BayesDel_noAF	Benign	-0.72
Cadd	Benign	14
Dann	Uncertain	0.99
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.79	T;T;.;T;T;.
MetaRNN	Benign	0.0032	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.31	T
REVEL	Benign	0.059
Polyphen		0.48, 0.43	.;P;.;.;.;B
Vest4		0.066, 0.071, 0.10
MVP		0.29
MPC		0.17
ClinPred		0.011	T
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

Other links and lift over

dbSNP: rs142507451; hg19: chr16-67694044; COSMIC: COSV99538103; COSMIC: COSV99538103;