rs138527794

Positions:

• chr16-67660013-G-A
• chr16-67660013-G-C

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001082486.2(ACD):​c.132C>T​(p.Gly44Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00228 in 1,606,706 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0023 (11 hom.)
• Consequence: ACD NM_001082486.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.334

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 16-67660013-G-A is Benign according to our data. Variant chr16-67660013-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 434068.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.334 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACD	NM_001082486.2	c.132C>T	p.Gly44Gly	synonymous_variant	2/12	ENST00000620761.6	NP_001075955.2
ACD	NM_022914.3	c.123C>T	p.Gly41Gly	synonymous_variant	2/12		NP_075065.3
ACD	NM_001410884.1	c.132C>T	p.Gly44Gly	synonymous_variant	2/11		NP_001397813.1
ACD	XR_429728.4	n.172C>T		non_coding_transcript_exon_variant	2/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACD	ENST00000620761.6	c.132C>T	p.Gly44Gly	synonymous_variant	2/12	1	NM_001082486.2	ENSP00000478084.1

Frequencies

GnomAD3 genomes AF: 0.00180 AC: 274 AN: 152230 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00268

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00476

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00184

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00254 AC: 591 AN: 232628 Hom.: 4 AF XY: 0.00269 AC XY: 345 AN XY: 128432

Gnomad AFR exome AF: 0.000141

Gnomad AMR exome AF: 0.00257

Gnomad ASJ exome AF: 0.0149

Gnomad EAS exome AF: 0.0000569

Gnomad SAS exome AF: 0.00298

Gnomad FIN exome AF: 0.000107

Gnomad NFE exome AF: 0.00238

Gnomad OTH exome AF: 0.00401

GnomAD4 exome AF: 0.00233 AC: 3383 AN: 1454358 Hom.: 11 Cov.: 34 AF XY: 0.00241 AC XY: 1743 AN XY: 723050

Gnomad4 AFR exome AF: 0.000300

Gnomad4 AMR exome AF: 0.00252

Gnomad4 ASJ exome AF: 0.0147

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00305

Gnomad4 FIN exome AF: 0.000241

Gnomad4 NFE exome AF: 0.00212

Gnomad4 OTH exome AF: 0.00333

GnomAD4 genome AF: 0.00179 AC: 273 AN: 152348 Hom.: 2 Cov.: 33 AF XY: 0.00192 AC XY: 143 AN XY: 74510

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.00268

Gnomad4 ASJ AF: 0.0153

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00455

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00184

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00291 Hom.: 0

Bravo AF: 0.00203

Asia WGS AF: 0.00289 AC: 11 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 20, 2019	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	ACD: BP4, BP7 -

Dyskeratosis congenita, autosomal dominant 6 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 12, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	6.5
DANN	Benign	0.92

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: rs138527794; hg19: chr16-67693916;