16-67657574-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001082486.2(ACD):c.*32T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0903 in 1,613,908 control chromosomes in the GnomAD database, including 7,411 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.079 (639 hom., cov: 33)
  • Exomes 𝑓: 0.091 (6772 hom.)
• Consequence: ACD NM_001082486.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.466

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]

CARMIL2 (HGNC:27089): (capping protein regulator and myosin 1 linker 2) This gene encodes a member of the CARMIL (capping protein, Arp2/3, myosin-I linker) family of proteins. The encoded protein interacts with and negatively regulates the heterodimeric capping protein and promotes cell migration. Reduced expression of this gene has been observed in human psoriasis patients. Mutations in this gene cause a human immunodeficiency syndrome characterized by smooth muscle tumors and impaired T-cell function. [provided by RefSeq, May 2017]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 16-67657574-A-T is Benign according to our data. Variant chr16-67657574-A-T is described in ClinVar as [Benign]. Clinvar id is 1235552.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.11 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACD	NM_001082486.2	c.*32T>A		3_prime_UTR_variant	12/12	ENST00000620761.6
CARMIL2	NM_001013838.3			downstream_gene_variant		ENST00000334583.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACD	ENST00000620761.6	c.*32T>A		3_prime_UTR_variant	12/12	1	NM_001082486.2	P1
CARMIL2	ENST00000334583.11			downstream_gene_variant		1	NM_001013838.3	A2

Frequencies

GnomAD3 genomes AF: 0.0787 AC: 11967 AN: 152148 Hom.: 638 Cov.: 33

Gnomad AFR AF: 0.0191

Gnomad AMI AF: 0.0680

Gnomad AMR AF: 0.115

Gnomad ASJ AF: 0.0767

Gnomad EAS AF: 0.0129

Gnomad SAS AF: 0.0796

Gnomad FIN AF: 0.149

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.101

Gnomad OTH AF: 0.0905

GnomAD3 exomes AF: 0.0943 AC: 23687 AN: 251172 Hom.: 1384 AF XY: 0.0924 AC XY: 12547 AN XY: 135768

Gnomad AFR exome AF: 0.0164

Gnomad AMR exome AF: 0.136

Gnomad ASJ exome AF: 0.0730

Gnomad EAS exome AF: 0.0107

Gnomad SAS exome AF: 0.0860

Gnomad FIN exome AF: 0.143

Gnomad NFE exome AF: 0.101

Gnomad OTH exome AF: 0.102

GnomAD4 exome AF: 0.0915 AC: 133703 AN: 1461642 Hom.: 6772 Cov.: 34 AF XY: 0.0916 AC XY: 66617 AN XY: 727118

Gnomad4 AFR exome AF: 0.0145

Gnomad4 AMR exome AF: 0.138

Gnomad4 ASJ exome AF: 0.0725

Gnomad4 EAS exome AF: 0.0113

Gnomad4 SAS exome AF: 0.0830

Gnomad4 FIN exome AF: 0.141

Gnomad4 NFE exome AF: 0.0940

Gnomad4 OTH exome AF: 0.0850

GnomAD4 genome AF: 0.0786 AC: 11973 AN: 152266 Hom.: 639 Cov.: 33 AF XY: 0.0806 AC XY: 6001 AN XY: 74432

Gnomad4 AFR AF: 0.0191

Gnomad4 AMR AF: 0.115

Gnomad4 ASJ AF: 0.0767

Gnomad4 EAS AF: 0.0131

Gnomad4 SAS AF: 0.0798

Gnomad4 FIN AF: 0.149

Gnomad4 NFE AF: 0.101

Gnomad4 OTH AF: 0.0938

Alfa AF: 0.0908 Hom.: 150

Bravo AF: 0.0736

Asia WGS AF: 0.0860 AC: 298 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Nov 12, 2023

This variant is classified as Benign based on local population frequency. This variant was detected in 26% of patients studied by a panel of primary immunodeficiencies. Number of patients: 25. Only high quality variants are reported. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 24, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
Cadd	Benign	5.0
Dann	Benign	0.86

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

LitVar

Other links and lift over

dbSNP: rs72556537; hg19: chr16-67691477;