rs753541585

Positions:

• chr10-110133615-CTAAA-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP6

The NM_016824.5(ADD3):​c.*2_*5del variant causes a stop retained, 3 prime UTR change. The variant allele was found at a frequency of 0.000251 in 1,570,816 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (0 hom.)
• Consequence: ADD3 NM_016824.5 stop_retained, 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 5.44

Genes affected

ADD3 (HGNC:245): (adducin 3) Adducins are heteromeric proteins composed of different subunits referred to as adducin alpha, beta and gamma. The three subunits are encoded by distinct genes and belong to a family of membrane skeletal proteins involved in the assembly of spectrin-actin network in erythrocytes and at sites of cell-cell contact in epithelial tissues. While adducins alpha and gamma are ubiquitously expressed, the expression of adducin beta is restricted to brain and hematopoietic tissues. Adducin, originally purified from human erythrocytes, was found to be a heterodimer of adducins alpha and beta. Polymorphisms resulting in amino acid substitutions in these two subunits have been associated with the regulation of blood pressure in an animal model of hypertension. Heterodimers consisting of alpha and gamma subunits have also been described. Structurally, each subunit is comprised of two distinct domains. The amino-terminal region is protease resistant and globular in shape, while the carboxy-terminal region is protease sensitive. The latter contains multiple phosphorylation sites for protein kinase C, the binding site for calmodulin, and is required for association with spectrin and actin. Alternatively spliced adducin gamma transcripts encoding different isoforms have been described. The functions of the different isoforms are not known. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 10-110133615-CTAAA-C is Benign according to our data. Variant chr10-110133615-CTAAA-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 445451.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADD3	NM_016824.5	c.*2_*5del		stop_retained_variant, 3_prime_UTR_variant	15/15	ENST00000356080.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADD3	ENST00000356080.9	c.*2_*5del		stop_retained_variant, 3_prime_UTR_variant	15/15	1	NM_016824.5	A1
ADD3	ENST00000277900.12	c.*2_*5del		stop_retained_variant, 3_prime_UTR_variant	14/14	1		P3
ADD3	ENST00000360162.7	c.*2_*5del		stop_retained_variant, 3_prime_UTR_variant	14/14	1		P3

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 40 AN: 152078 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000359 AC: 77 AN: 214620 Hom.: 0 AF XY: 0.000349 AC XY: 41 AN XY: 117378

Gnomad AFR exome AF: 0.000138

Gnomad AMR exome AF: 0.000153

Gnomad ASJ exome AF: 0.00476

Gnomad EAS exome AF: 0.000124

Gnomad SAS exome AF: 0.000123

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000242

Gnomad OTH exome AF: 0.000594

GnomAD4 exome AF: 0.000250 AC: 354 AN: 1418738 Hom.: 0 AF XY: 0.000253 AC XY: 178 AN XY: 703960

Gnomad4 AFR exome AF: 0.0000963

Gnomad4 AMR exome AF: 0.000113

Gnomad4 ASJ exome AF: 0.00412

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.000101

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000155

Gnomad4 OTH exome AF: 0.000666

GnomAD4 genome AF: 0.000263 AC: 40 AN: 152078 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74288

Gnomad4 AFR AF: 0.0000966

Gnomad4 AMR AF: 0.000197

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.000956

Alfa AF: 0.000832 Hom.: 1

Bravo AF: 0.000264

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 22, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Aug 17, 2023	- -

Computational scores

Source: dbNSFP v4.3

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: rs753541585; hg19: chr10-111893373;