16-67657613-G-A

Position:

chr16-67657613-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001082486.2(ACD):c.1370C>T(p.Pro457Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000489 in 1,614,130 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000050 ( 0 hom. )

Consequence

ACD
NM_001082486.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.709

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:

CARMIL2 (HGNC:27089): (capping protein regulator and myosin 1 linker 2) This gene encodes a member of the CARMIL (capping protein, Arp2/3, myosin-I linker) family of proteins. The encoded protein interacts with and negatively regulates the heterodimeric capping protein and promotes cell migration. Reduced expression of this gene has been observed in human psoriasis patients. Mutations in this gene cause a human immunodeficiency syndrome characterized by smooth muscle tumors and impaired T-cell function. [provided by RefSeq, May 2017]

CARMIL2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.04415533).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACD	NM_001082486.2 linkuse as main transcript	c.1370C>T	p.Pro457Leu	missense_variant	12/12	ENST00000620761.6	NP_001075955.2
CARMIL2	NM_001013838.3 linkuse as main transcript			downstream_gene_variant		ENST00000334583.11	NP_001013860.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACD	ENST00000620761.6 linkuse as main transcript	c.1370C>T	p.Pro457Leu	missense_variant	12/12	1	NM_001082486.2	ENSP00000478084	P1	Q96AP0-3
CARMIL2	ENST00000334583.11 linkuse as main transcript			downstream_gene_variant		1	NM_001013838.3	ENSP00000334958	A2	Q6F5E8-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000438

AC:

AN:

251354

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135858

show subpopulations

Gnomad AFR exome

AF:

0.000123

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:

0.0000792

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000499

AC:

AN:

1461830

Hom.:

Cov.:

AF XY:

0.0000454

AC XY:

AN XY:

727214

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000656

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152300

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000545

Hom.:

Bravo

AF:

0.0000378

ESP6500AA

AF:

0.000455

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000577

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 16, 2021

DNA sequence analysis of the ACD gene demonstrated a sequence change, c.1370C>T, in exon 12 that results in an amino acid change, p.Pro457Leu. This sequence change has been described in gnomAD with a frequency of 0.012% in the African sub-population (dbSNP rs150387011). The p.Pro457Leu change affects a poorly conserved amino acid residue located in a domain of the ACD protein that is not known to be functional. The p.Pro457Leu substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change does not appear to have been previously described in patients with ACD-related disorders. Due to the lack of sufficient evidences, the clinical significance of the p.Pro457Leu change remains unknown at this time. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 02, 2021

The p.P543L variant (also known as c.1628C>T), located in coding exon 12 of the ACD gene, results from a C to T substitution at nucleotide position 1628. The proline at codon 543 is replaced by leucine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Dyskeratosis congenita, autosomal dominant 6

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 543 of the ACD protein (p.Pro543Leu). This variant is present in population databases (rs150387011, gnomAD 0.008%). 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: 1337912). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Benign

0.74

DEOGEN2

Uncertain

0.49

.;T;T;T;T;.

Eigen

Benign

-0.79

Eigen_PC

Benign

-0.77

FATHMM_MKL

Benign

0.057

LIST_S2

Benign

0.34

T;T;.;T;T;.

M_CAP

Benign

0.011

MetaRNN

Benign

0.044

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

.;N;.;.;.;.

MutationTaster

Benign

0.82

N;N

PrimateAI

Benign

0.31

REVEL

Benign

0.019

Sift4G

Benign

0.19

.;T;T;.;T;.

Polyphen

0.30, 0.43

.;B;.;.;.;B

Vest4

0.20, 0.21, 0.21

MVP

0.40

MPC

0.10

ClinPred

0.054

GERP RS

2.6

Varity_R

0.034

gMVP

0.069

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