rs1555542235

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The ENST00000620761.6(ACD):​c.737C>A​(p.Thr246Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

ACD
ENST00000620761.6 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.241
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.08056906).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ACDNM_001082486.2 linkuse as main transcriptc.737C>A p.Thr246Lys missense_variant 8/12 ENST00000620761.6 NP_001075955.2
ACDNM_022914.3 linkuse as main transcriptc.728C>A p.Thr243Lys missense_variant 8/12 NP_075065.3
ACDNM_001410884.1 linkuse as main transcriptc.737C>A p.Thr246Lys missense_variant 8/11 NP_001397813.1
ACDXR_429728.4 linkuse as main transcriptn.793C>A non_coding_transcript_exon_variant 8/9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ACDENST00000620761.6 linkuse as main transcriptc.737C>A p.Thr246Lys missense_variant 8/121 NM_001082486.2 ENSP00000478084 P1Q96AP0-3

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
34
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Dyskeratosis congenita, autosomal dominant 6 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 23, 2017This variant is not present in population databases (ExAC no frequency). 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with ACD-related disease. This sequence change replaces threonine with lysine at codon 332 of the ACD protein (p.Thr332Lys). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and lysine. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.14
BayesDel_addAF
Benign
-0.28
T
BayesDel_noAF
Benign
-0.64
CADD
Benign
10
DANN
Benign
0.91
DEOGEN2
Benign
0.22
.;T;T;T;T;.
Eigen
Benign
-0.76
Eigen_PC
Benign
-0.76
FATHMM_MKL
Benign
0.060
N
LIST_S2
Benign
0.60
T;T;.;T;T;.
M_CAP
Benign
0.021
T
MetaRNN
Benign
0.081
T;T;T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.6
.;L;.;.;.;.
MutationTaster
Benign
1.0
N;N
PrimateAI
Benign
0.38
T
PROVEAN
Benign
-2.1
N;.;.;N;.;.
REVEL
Benign
0.016
Sift
Uncertain
0.020
D;.;.;D;.;.
Sift4G
Benign
0.14
.;T;T;.;D;.
Polyphen
0.24, 0.36
.;B;.;.;.;B
Vest4
0.22, 0.19, 0.21
MutPred
0.36
.;Gain of methylation at T332 (P = 0.001);.;.;.;.;
MVP
0.48
MPC
0.17
ClinPred
0.090
T
GERP RS
1.2
Varity_R
0.054
gMVP
0.24

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.

Other links and lift over

dbSNP: rs1555542235; hg19: chr16-67692628; API