rs201441120

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_001082486.2(ACD):c.1213C>A(p.Pro405Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000496 in 1,613,898 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P405L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000053 ( 0 hom. )

Consequence

ACD
NM_001082486.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:3O:1

Conservation

PhyloP100: 2.06

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 Likely_benign. Variant got -1 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.31799716).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ACD	NM_001082486.2 linkuse as main transcript	c.1213C>A	p.Pro405Thr	missense_variant	11/12	ENST00000620761.6
ACD	NM_022914.3 linkuse as main transcript	c.1204C>A	p.Pro402Thr	missense_variant	11/12
ACD	NM_001410884.1 linkuse as main transcript	c.1126C>A	p.Pro376Thr	missense_variant	10/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACD	ENST00000620761.6 linkuse as main transcript	c.1213C>A	p.Pro405Thr	missense_variant	11/12	1	NM_001082486.2	P1	Q96AP0-3

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000517

AC:

AN:

251316

Hom.:

AF XY:

0.0000515

AC XY:

AN XY:

135872

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.000106

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000527

AC:

AN:

1461738

Hom.:

Cov.:

AF XY:

0.0000399

AC XY:

AN XY:

727174

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000751

Gnomad4 NFE exome

AF:

0.0000638

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152160

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000486

Hom.:

Bravo

AF:

0.0000264

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Dyskeratosis congenita, autosomal dominant 6

Uncertain:2Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	May 20, 2023	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this missense change does not substantially affect ACD function (PMID: 25233904). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ACD protein function. ClinVar contains an entry for this variant (Variation ID: 208984). This missense change has been observed in individual(s) with Hoyeraal-Hreidarsson syndrome (PMID: 25233904). This variant is present in population databases (rs201441120, gnomAD 0.01%). This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 491 of the ACD protein (p.Pro491Thr). -
not provided, no classification provided	literature only	GeneReviews	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Apr 29, 2022	ACD c.1213C>A has been previously identified in an individual with dyskeratosis congenita, autosomal recessive 7 who carried a second ACD variant on the opposite allele. This individual's healthy mother carried c.1213C>A in the heterozygous state and had normal telomere length. This variant has been reported in ClinVar (Variation ID: 208984) and is rare (<0.1%) in a large population dataset (gnomAD: 13/251316 total alleles; 0.005173%; no homozygotes). In vitro functional studies indicate that p.Pro405Thr may result in a modest decrease in binding between ACD and TIN2,however the clinical significance of this finding is uncertain. The proline residue at this position is evolutionarily conserved in most mammalian species assessed. We consider the clinical significance of ACD c.1213C>A to be uncertain at this time. -

Dyskeratosis congenita, autosomal recessive 7

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 2014

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Feb 06, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.18

Cadd

Uncertain

Dann

Uncertain

1.0

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.68

T;T;.;T;.

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.32

T;T;T;T;T

MetaSVM

Uncertain

-0.12

MutationTaster

Benign

0.91

D;D

PrimateAI

Benign

0.33

REVEL

Uncertain

0.46

Polyphen

1.0

.;D;.;.;D

Vest4

0.23, 0.23

MVP

0.82

MPC

0.50

ClinPred

0.59

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.34

gMVP

0.28

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