rs72549181

Variant names:

• chr16-67658583-G-A
• rs72549181
• NM_001082486.2:c.801C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-67658583-G-A
• chr16-67658583-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001082486.2(ACD):​c.801C>T​(p.Ala267Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000911 in 1,572,944 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A267A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0049 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00048 (4 hom.)
• Consequence: ACD NM_001082486.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.412
• Publications: 1 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 16-67658583-G-A is Benign according to our data. Variant chr16-67658583-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 542420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.412 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00495 (753/152268) while in subpopulation AFR AF = 0.0173 (718/41542). AF 95% confidence interval is 0.0162. There are 1 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 GnomAdExome4 at 4 AR,AD gene

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.801C>T	p.Ala267Ala	synonymous	Exon 9 of 12	NP_001075955.2	Q96AP0-3
	ACD	NM_022914.3		c.792C>T	p.Ala264Ala	synonymous	Exon 9 of 12	NP_075065.3	Q96AP0-2
	ACD	NM_001410884.1		c.742+137C>T		intron	N/A	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.801C>T	p.Ala267Ala	synonymous	Exon 9 of 12	ENSP00000478084.1	Q96AP0-3
	ACD	ENST00000695659.1		c.801C>T	p.Ala267Ala	synonymous	Exon 9 of 12	ENSP00000512089.1	A0A8Q3SHY1
	ACD	ENST00000219251.13	TSL:2	c.792C>T	p.Ala264Ala	synonymous	Exon 9 of 12	ENSP00000219251.8	Q96AP0-2

Frequencies

GnomAD3 genomes AF: 0.00495 AC: 753 AN: 152150 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0173

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

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: 0.0000882

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00151 AC: 329 AN: 217814 AF XY: 0.00110

Gnomad AFR exome AF: 0.0180

Gnomad AMR exome AF: 0.00120

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000202

Gnomad OTH exome AF: 0.000585

GnomAD4 exome AF: 0.000479 AC: 680 AN: 1420676 Hom.: 4 Cov.: 34 AF XY: 0.000393 AC XY: 276 AN XY: 701760

African (AFR) AF: 0.0160 AC: 521 AN: 32554

American (AMR) AF: 0.00135 AC: 55 AN: 40824

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22922

East Asian (EAS) AF: 0.00 AC: 0 AN: 39372

South Asian (SAS) AF: 0.0000127 AC: 1 AN: 79024

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51598

Middle Eastern (MID) AF: 0.000902 AC: 5 AN: 5544

European-Non Finnish (NFE) AF: 0.0000174 AC: 19 AN: 1090302

Other (OTH) AF: 0.00135 AC: 79 AN: 58536

GnomAD4 genome AF: 0.00495 AC: 753 AN: 152268 Hom.: 1 Cov.: 33 AF XY: 0.00473 AC XY: 352 AN XY: 74442

African (AFR) AF: 0.0173 AC: 718 AN: 41542

American (AMR) AF: 0.00157 AC: 24 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68016

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.00285 Hom.: 1

Bravo AF: 0.00541

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	ACD-related disorder (1)
-	-	1	Dyskeratosis congenita, autosomal dominant 6 (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.7
DANN	Benign	0.63
PhyloP100		-0.41
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs72549181; hg19: chr16-67692486;