16-67660013-G-A

Variant names:

• chr16-67660013-G-A
• rs138527794
• NM_001082486.2:c.132C>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001082486.2(ACD):​c.132C>T​(p.Gly44Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00228 in 1,606,706 control chromosomes in the GnomAD database, including 13 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. G44G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0018 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0023 (11 hom.)
• Consequence: ACD NM_001082486.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.334
• 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):

• 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 16-67660013-G-A is Benign according to our data. Variant chr16-67660013-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 434068.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.334 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 2 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACD	NM_001082486.2	MANE Select	c.132C>T	p.Gly44Gly	synonymous	Exon 2 of 12	NP_001075955.2
	ACD	NM_022914.3		c.123C>T	p.Gly41Gly	synonymous	Exon 2 of 12	NP_075065.3
	ACD	NM_001410884.1		c.132C>T	p.Gly44Gly	synonymous	Exon 2 of 11	NP_001397813.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACD	ENST00000620761.6	TSL:1 MANE Select	c.132C>T	p.Gly44Gly	synonymous	Exon 2 of 12	ENSP00000478084.1
	ACD	ENST00000695659.1		c.132C>T	p.Gly44Gly	synonymous	Exon 2 of 12	ENSP00000512089.1
	ACD	ENST00000219251.13	TSL:2	c.123C>T	p.Gly41Gly	synonymous	Exon 2 of 12	ENSP00000219251.8

Frequencies

GnomAD3 genomes AF: 0.00180 AC: 274 AN: 152230 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00268

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00476

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00184

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00254 AC: 591 AN: 232628 AF XY: 0.00269

Gnomad AFR exome AF: 0.000141

Gnomad AMR exome AF: 0.00257

Gnomad ASJ exome AF: 0.0149

Gnomad EAS exome AF: 0.0000569

Gnomad FIN exome AF: 0.000107

Gnomad NFE exome AF: 0.00238

Gnomad OTH exome AF: 0.00401

GnomAD4 exome AF: 0.00233 AC: 3383 AN: 1454358 Hom.: 11 Cov.: 34 AF XY: 0.00241 AC XY: 1743 AN XY: 723050

African (AFR) AF: 0.000300 AC: 10 AN: 33350

American (AMR) AF: 0.00252 AC: 112 AN: 44360

Ashkenazi Jewish (ASJ) AF: 0.0147 AC: 381 AN: 25972

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39590

South Asian (SAS) AF: 0.00305 AC: 262 AN: 85988

European-Finnish (FIN) AF: 0.000241 AC: 12 AN: 49886

Middle Eastern (MID) AF: 0.00834 AC: 48 AN: 5754

European-Non Finnish (NFE) AF: 0.00212 AC: 2357 AN: 1109394

Other (OTH) AF: 0.00333 AC: 200 AN: 60064

GnomAD4 genome AF: 0.00179 AC: 273 AN: 152348 Hom.: 2 Cov.: 33 AF XY: 0.00192 AC XY: 143 AN XY: 74510

African (AFR) AF: 0.000385 AC: 16 AN: 41574

American (AMR) AF: 0.00268 AC: 41 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0153 AC: 53 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00455 AC: 22 AN: 4830

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10630

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00184 AC: 125 AN: 68032

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00291 Hom.: 0

Bravo AF: 0.00203

Asia WGS AF: 0.00289 AC: 11 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Dyskeratosis congenita, autosomal dominant 6 (2)
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	6.5
DANN	Benign	0.92
PhyloP100		-0.33
PromoterAI		-0.22	Neutral
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs138527794; hg19: chr16-67693916;