Genetic Variant ACD:c.-97C>T (chr16-67660317-G-A) – ACMG Classification: Benign (-18 pts)

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The ENST00000219251.13(ACD):c.-97C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000952 in 1,608,210 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0050 ( 9 hom., cov: 33)

Exomes 𝑓: 0.00053 ( 5 hom. )

Consequence

ACD
ENST00000219251.13 5_prime_UTR

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.59

Publications

1 publications found

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 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

ACD links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.46).

BP6

Variant 16-67660317-G-A is Benign according to our data. Variant chr16-67660317-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 475767.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.005 (761/152308) while in subpopulation AFR AF = 0.0174 (722/41568). AF 95% confidence interval is 0.0163. There are 9 homozygotes in GnomAd4. There are 352 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 9 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000219251.13. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
ACD	NM_001082486.2	MANE Select	c.-97C>T	upstream_gene	N/A	NP_001075955.2
ACD	NM_022914.3		c.-97C>T	upstream_gene	N/A	NP_075065.3
ACD	NM_001410884.1		c.-97C>T	upstream_gene	N/A	NP_001397813.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
ACD	ENST00000219251.13	TSL:2	c.-97C>T	5_prime_UTR	Exon 1 of 12	ENSP00000219251.8
ACD	ENST00000602382.6	TSL:5	c.-97C>T	5_prime_UTR	Exon 1 of 12	ENSP00000473313.2
ACD	ENST00000602860.6	TSL:5	n.447C>T	non_coding_transcript_exon	Exon 1 of 9

Frequencies

GnomAD3 genomes

AF:

0.00500

AC:

761

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0174

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00222

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:

0.0000294

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00128

AC:

300

AN:

234382

AF XY:

0.000920

show subpopulations

Gnomad AFR exome

AF:

0.0179

Gnomad AMR exome

AF:

0.00141

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000289

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000529

AC:

770

AN:

1455902

Hom.:

Cov.:

AF XY:

0.000469

AC XY:

340

AN XY:

724328

show subpopulations

African (AFR)

AF:

0.0188

AC:

623

AN:

33186

American (AMR)

AF:

0.00142

AC:

AN:

43684

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25984

East Asian (EAS)

AF:

0.00

AC:

AN:

39650

South Asian (SAS)

AF:

0.0000465

AC:

AN:

85960

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51200

Middle Eastern (MID)

AF:

0.000709

AC:

AN:

5644

European-Non Finnish (NFE)

AF:

0.00000900

AC:

AN:

1110514

Other (OTH)

AF:

0.00112

AC:

AN:

60080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.537

Heterozygous variant carriers

118

177

236

295

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00500

AC:

761

AN:

152308

Hom.:

Cov.:

AF XY:

0.00473

AC XY:

352

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.0174

AC:

722

AN:

41568

American (AMR)

AF:

0.00222

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5156

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68030

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

118

158

197

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00139

Hom.:

Bravo

AF:

0.00583

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Dyskeratosis congenita, autosomal dominant 6 (1)

Inborn genetic diseases (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Benign

0.84

PhyloP100

1.6

PromoterAI

0.14

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over