16-67658928-C-A

Variant names:

• chr16-67658928-C-A
• rs571116752
• NM_001082486.2:c.645G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001082486.2(ACD):​c.645G>T​(p.Thr215Thr) variant causes a splice region, synonymous 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. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. T215T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ACD NM_001082486.2 splice_region, synonymous
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.63
• Publications: 0 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):

• ACD-related short telomere syndrome

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001082486.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACD	NM_001082486.2	MANE Select	c.645G>T	p.Thr215Thr	splice_region synonymous	Exon 7 of 12	NP_001075955.2	Q96AP0-3
	ACD	NM_022914.3		c.636G>T	p.Thr212Thr	splice_region synonymous	Exon 7 of 12	NP_075065.3	Q96AP0-2
	ACD	NM_001410884.1		c.645G>T	p.Thr215Thr	splice_region synonymous	Exon 7 of 11	NP_001397813.1	A0A8Q3WM11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACD	ENST00000620761.6	TSL:1 MANE Select	c.645G>T	p.Thr215Thr	splice_region synonymous	Exon 7 of 12	ENSP00000478084.1	Q96AP0-3
	ACD	ENST00000695659.1		c.645G>T	p.Thr215Thr	splice_region synonymous	Exon 7 of 12	ENSP00000512089.1	A0A8Q3SHY1
	ACD	ENST00000219251.13	TSL:2	c.636G>T	p.Thr212Thr	splice_region synonymous	Exon 7 of 12	ENSP00000219251.8	Q96AP0-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	21
DANN	Benign	0.91
PhyloP100		1.6
PromoterAI		-0.022	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.67		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.67		Position offset: 0

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

Other links and lift over

dbSNP: rs571116752; hg19: chr16-67692831;