rs6979

Positions:

chr16-67657765-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001082486.2(ACD):c.1295T>C(p.Val432Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.497 in 1,613,744 control chromosomes in the GnomAD database, including 209,358 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.60 ( 29938 hom., cov: 32)

Exomes 𝑓: 0.49 ( 179420 hom. )

Consequence

ACD
NM_001082486.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5O:1

Conservation

PhyloP100: -0.0910

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.0911076E-6).

BP6

Variant 16-67657765-A-G is Benign according to our data. Variant chr16-67657765-A-G is described in ClinVar as [Benign]. Clinvar id is 1167321.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.885 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACD	NM_001082486.2 link	c.1295T>C	p.Val432Ala	missense_variant	11/12	ENST00000620761.6	NP_001075955.2	Q96AP0-3
ACD	NM_022914.3 link	c.1286T>C	p.Val429Ala	missense_variant	11/12		NP_075065.3	Q96AP0-2
ACD	NM_001410884.1 link	c.1208T>C	p.Val403Ala	missense_variant	10/11		NP_001397813.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACD	ENST00000620761.6 link	c.1295T>C	p.Val432Ala	missense_variant	11/12	1	NM_001082486.2	ENSP00000478084.1		Q96AP0-3

Frequencies

GnomAD3 genomes

AF:

0.595

AC:

90426

AN:

151964

Hom.:

29887

Cov.:

show subpopulations

Gnomad AFR

AF:

0.893

Gnomad AMI

AF:

0.497

Gnomad AMR

AF:

0.510

Gnomad ASJ

AF:

0.567

Gnomad EAS

AF:

0.153

Gnomad SAS

AF:

0.557

Gnomad FIN

AF:

0.525

Gnomad MID

AF:

0.661

Gnomad NFE

AF:

0.483

Gnomad OTH

AF:

0.569

GnomAD3 exomes

AF:

0.501

AC:

125898

AN:

251212

Hom.:

34446

AF XY:

0.501

AC XY:

68057

AN XY:

135806

show subpopulations

Gnomad AFR exome

AF:

0.900

Gnomad AMR exome

AF:

0.436

Gnomad ASJ exome

AF:

0.552

Gnomad EAS exome

AF:

0.151

Gnomad SAS exome

AF:

0.576

Gnomad FIN exome

AF:

0.513

Gnomad NFE exome

AF:

0.493

Gnomad OTH exome

AF:

0.522

GnomAD4 exome

AF:

0.486

AC:

710713

AN:

1461662

Hom.:

179420

Cov.:

AF XY:

0.489

AC XY:

355463

AN XY:

727140

show subpopulations

Gnomad4 AFR exome

AF:

0.910

Gnomad4 AMR exome

AF:

0.448

Gnomad4 ASJ exome

AF:

0.560

Gnomad4 EAS exome

AF:

0.155

Gnomad4 SAS exome

AF:

0.564

Gnomad4 FIN exome

AF:

0.512

Gnomad4 NFE exome

AF:

0.476

Gnomad4 OTH exome

AF:

0.504

GnomAD4 genome

AF:

0.595

AC:

90532

AN:

152082

Hom.:

29938

Cov.:

AF XY:

0.593

AC XY:

44107

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.893

Gnomad4 AMR

AF:

0.509

Gnomad4 ASJ

AF:

0.567

Gnomad4 EAS

AF:

0.154

Gnomad4 SAS

AF:

0.554

Gnomad4 FIN

AF:

0.525

Gnomad4 NFE

AF:

0.483

Gnomad4 OTH

AF:

0.574

Alfa

AF:

0.516

Hom.:

38945

Bravo

AF:

0.601

TwinsUK

AF:

0.467

AC:

1733

ALSPAC

AF:

0.462

AC:

1782

ESP6500AA

AF:

0.885

AC:

3889

ESP6500EA

AF:

0.489

AC:

4205

ExAC

AF:

0.515

AC:

62557

Asia WGS

AF:

0.450

AC:

1568

AN:

3478

EpiCase

AF:

0.503

EpiControl

AF:

0.502

ClinVar

Significance: Benign

Submissions summary: Benign:5Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2Other:1

not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -

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	Feb 01, 2024	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jan 24, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 68% of patients studied by a panel of primary immunodeficiencies. Number of patients: 65. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.81

BayesDel_noAF

Benign

-0.79

CADD

Benign

5.5

DANN

Benign

0.77

DEOGEN2

Benign

0.11

.;T;T;T;T;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.96

FATHMM_MKL

Benign

0.0068

LIST_S2

Benign

0.21

T;T;.;T;T;.

MetaRNN

Benign

0.0000011

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.90

.;N;.;.;.;.

PrimateAI

Benign

0.32

REVEL

Benign

0.035

Sift4G

Benign

0.93

.;T;T;.;T;.

Polyphen

0.0

.;B;.;.;.;B

Vest4

0.058, 0.086, 0.051

MPC

0.11

ClinPred

0.0080

GERP RS

1.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.016

gMVP

0.082

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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