rs797045144

Variant names:

• chr16-67659785-CCTT-C
• rs797045144
• NM_001082486.2:c.250_252delAAG

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM4_Supporting PP5_Moderate

The NM_001082486.2(ACD):​c.250_252delAAG​(p.Lys84del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000687 in 1,455,008 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. K84K) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: ACD NM_001082486.2 conservative_inframe_deletion
• Clinical Significance: Pathogenic criteria provided, single submitter P:3 O:1
• Conservation: PhyloP100: 3.12
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• dyskeratosis congenita, autosomal dominant 6

  Inheritance: AR, AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P
• hereditary isolated aplastic anemia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Hoyeraal-Hreidarsson syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001082486.2. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 16-67659785-CCTT-C is Pathogenic according to our data. Variant chr16-67659785-CCTT-C is described in ClinVar as [Pathogenic]. Clinvar id is 208983.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACD	NM_001082486.2	c.250_252delAAG	p.Lys84del	conservative_inframe_deletion	Exon 3 of 12	ENST00000620761.6	NP_001075955.2
ACD	NM_022914.3	c.241_243delAAG	p.Lys81del	conservative_inframe_deletion	Exon 3 of 12		NP_075065.3
ACD	NM_001410884.1	c.250_252delAAG	p.Lys84del	conservative_inframe_deletion	Exon 3 of 11		NP_001397813.1
ACD	XR_429728.4	n.290_292delAAG		non_coding_transcript_exon_variant	Exon 3 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACD	ENST00000620761.6	c.250_252delAAG	p.Lys84del	conservative_inframe_deletion	Exon 3 of 12	1	NM_001082486.2	ENSP00000478084.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000687 AC: 10 AN: 1455008 Hom.: 0 AF XY: 0.00000692 AC XY: 5 AN XY: 722670

African (AFR) AF: 0.00 AC: 0 AN: 33366

American (AMR) AF: 0.00 AC: 0 AN: 44586

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25938

East Asian (EAS) AF: 0.00 AC: 0 AN: 39526

South Asian (SAS) AF: 0.00 AC: 0 AN: 86042

European-Finnish (FIN) AF: 0.0000190 AC: 1 AN: 52514

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.00000813 AC: 9 AN: 1107230

Other (OTH) AF: 0.00 AC: 0 AN: 60058

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Dyskeratosis congenita, autosomal dominant 6 Pathogenic:2 Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Aug 31, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects ACD function (PMID: 25205116, 25233904, 27807141). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 208983). This variant has been observed in individual(s) with clinical features of dyskeratosis congenita (PMID: 25205116, 25233904, 31515401; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This variant, c.508_510del, results in the deletion of 1 amino acid(s) of the ACD protein (p.Lys170del), but otherwise preserves the integrity of the reading frame. -

Oct 30, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Dyskeratosis congenita, autosomal recessive 7 Pathogenic:1

Oct 30, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.1
Mutation Taster		=59/41	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs797045144; hg19: chr16-67693688;