16-67658928-C-T

Position:

chr16-67658928-C-T

Variant summary

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

The NM_001082486.2(ACD):c.645G>A(p.Thr215Thr) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000316 in 1,613,518 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

ACD
NM_001082486.2 splice_region, synonymous

Scores

Splicing: ADA: 1.000

Clinical Significance

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

Conservation

PhyloP100: 1.63

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:

ACD (HGNC:):

ACD links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACD	NM_001082486.2 linkuse as main transcript	c.645G>A	p.Thr215Thr	splice_region_variant, synonymous_variant	7/12	ENST00000620761.6	NP_001075955.2	Q96AP0-3
ACD	NM_022914.3 linkuse as main transcript	c.636G>A	p.Thr212Thr	splice_region_variant, synonymous_variant	7/12		NP_075065.3	Q96AP0-2
ACD	NM_001410884.1 linkuse as main transcript	c.645G>A	p.Thr215Thr	splice_region_variant, synonymous_variant	7/11		NP_001397813.1
ACD	XR_429728.4 linkuse as main transcript	n.685G>A		splice_region_variant, non_coding_transcript_exon_variant	7/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACD	ENST00000620761.6 linkuse as main transcript	c.645G>A	p.Thr215Thr	splice_region_variant, synonymous_variant	7/12	1	NM_001082486.2	ENSP00000478084.1		Q96AP0-3

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152150

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:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000719

AC:

AN:

250334

Hom.:

AF XY:

0.0000813

AC XY:

AN XY:

135288

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:

0.000425

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.000491

GnomAD4 exome

AF:

0.0000335

AC:

AN:

1461250

Hom.:

Cov.:

AF XY:

0.0000481

AC XY:

AN XY:

726910

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000406

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000108

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152268

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74452

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:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Dyskeratosis congenita, autosomal dominant 6

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The observed synonymous variant c.645G>A (p.Thr215) in the ACD gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This p.Thr215 type of mutation causes no change in the protein that is produced, which is why it's considered as synonymous mutation. This variant has been reported to the ClinVar database as Uncertain significance. This variant is reported with the allele frequency 0.0004% in the gnomAD Exomes. It is predicted to be damaging as per SpliceAI prediction tool. For these reasons, this variant has been classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 14, 2023	This sequence change affects codon 301 of the ACD mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the ACD protein. This variant also falls at the last nucleotide of exon 7, which is part of the consensus splice site for this exon. This variant is present in population databases (rs571116752, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with ACD-related conditions. ClinVar contains an entry for this variant (Variation ID: 648536). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 01, 2021

The c.903G>A (p.T301T) alteration is located in exon 7 (coding exon 7) of the ACD gene. This alteration consists of a G to A substitution at nucleotide position 903. This nucleotide substitution does not change the amino acid at codon 301. However, this change occurs in the last nucleotide of Exon 7 (c.752_903) which makes it likely to have some effect on normal mRNA splicing. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Benign

0.92

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

SpliceAI score (max)

0.64

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.64

Position offset: 0

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