rs147189192

Variant names:

• chr16-67658269-C-T
• rs147189192
• NM_001082486.2:c.923G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001082486.2(ACD):​c.923G>A​(p.Gly308Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00122 in 1,613,710 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict 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. G308G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0063 (5 hom., cov: 33)
  • Exomes 𝑓: 0.00069 (14 hom.)
• Consequence: ACD NM_001082486.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.31
• 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):

• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0036298037).
• BP6: Variant 16-67658269-C-T is Benign according to our data. Variant chr16-67658269-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 475764.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 = 0.00626 (953/152246) while in subpopulation AFR AF = 0.0214 (888/41540). AF 95% confidence interval is 0.0202. There are 5 homozygotes in GnomAd4. There are 443 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR,AD,SD 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.923G>A	p.Gly308Glu	missense	Exon 10 of 12	NP_001075955.2	Q96AP0-3
	ACD	NM_022914.3		c.914G>A	p.Gly305Glu	missense	Exon 10 of 12	NP_075065.3	Q96AP0-2
	ACD	NM_001410884.1		c.836G>A	p.Gly279Glu	missense	Exon 9 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.923G>A	p.Gly308Glu	missense	Exon 10 of 12	ENSP00000478084.1	Q96AP0-3
	ACD	ENST00000695659.1		c.923G>A	p.Gly308Glu	missense	Exon 10 of 12	ENSP00000512089.1	A0A8Q3SHY1
	ACD	ENST00000219251.13	TSL:2	c.914G>A	p.Gly305Glu	missense	Exon 10 of 12	ENSP00000219251.8	Q96AP0-2

Frequencies

GnomAD3 genomes AF: 0.00626 AC: 953 AN: 152128 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.0215

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.000289

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: 0.00622

GnomAD2 exomes AF: 0.00147 AC: 367 AN: 250392 AF XY: 0.00104

Gnomad AFR exome AF: 0.0206

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.000398

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000884

Gnomad OTH exome AF: 0.000979

GnomAD4 exome AF: 0.000690 AC: 1008 AN: 1461464 Hom.: 14 Cov.: 34 AF XY: 0.000615 AC XY: 447 AN XY: 727026

African (AFR) AF: 0.0237 AC: 793 AN: 33480

American (AMR) AF: 0.000693 AC: 31 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000383 AC: 10 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53006

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5766

European-Non Finnish (NFE) AF: 0.0000674 AC: 75 AN: 1112002

Other (OTH) AF: 0.00142 AC: 86 AN: 60394

GnomAD4 genome AF: 0.00626 AC: 953 AN: 152246 Hom.: 5 Cov.: 33 AF XY: 0.00595 AC XY: 443 AN XY: 74438

African (AFR) AF: 0.0214 AC: 888 AN: 41540

American (AMR) AF: 0.00288 AC: 44 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68000

Other (OTH) AF: 0.00616 AC: 13 AN: 2112

Alfa AF: 0.00365 Hom.: 9

Bravo AF: 0.00752

ESP6500AA AF: 0.0196 AC: 86

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00186 AC: 226

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Dyskeratosis congenita, autosomal dominant 6 (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.10
DANN	Benign	0.85
DEOGEN2	Benign	0.22	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.053	N
LIST_S2	Benign	0.56	T
MetaRNN	Benign	0.0036	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
PhyloP100		-1.3
PrimateAI	Benign	0.32	T
REVEL	Benign	0.080
Sift4G	Benign	0.19	T
Polyphen		0.92	P
Vest4		0.065
MVP		0.31
MPC		0.12
ClinPred		0.013	T
GERP RS		-5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.028
gMVP		0.19
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: rs147189192; hg19: chr16-67692172; COSMIC: COSV99029543; COSMIC: COSV99029543;