rs3731566

Variant names:

• chr10-110126331-G-A
• rs3731566
• NM_016824.5:c.1522-86G>A

Your query was ambiguous. Multiple possible variants found:

• chr10-110126331-G-A
• chr10-110126331-G-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_016824.5(ADD3):​c.1522-86G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.646 in 1,003,096 control chromosomes in the GnomAD database, including 219,547 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.71 (40424 hom., cov: 31)
  • Exomes 𝑓: 0.63 (179123 hom.)
• Consequence: ADD3 NM_016824.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0260
• Publications: 17 publications found

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]

ADD3 Gene-Disease associations (from GenCC):

• cerebral palsy, spastic quadriplegic, 3

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• complex neurodevelopmental disorder with motor features

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen
• spastic quadriplegic cerebral palsy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.975 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADD3	NM_016824.5	c.1522-86G>A		intron_variant	Intron 11 of 14	ENST00000356080.9	NP_058432.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADD3	ENST00000356080.9	c.1522-86G>A		intron_variant	Intron 11 of 14	1	NM_016824.5	ENSP00000348381.4

Frequencies

GnomAD3 genomes AF: 0.708 AC: 107542 AN: 151970 Hom.: 40346 Cov.: 31

Gnomad AFR AF: 0.925

Gnomad AMI AF: 0.599

Gnomad AMR AF: 0.754

Gnomad ASJ AF: 0.658

Gnomad EAS AF: 0.998

Gnomad SAS AF: 0.870

Gnomad FIN AF: 0.504

Gnomad MID AF: 0.744

Gnomad NFE AF: 0.567

Gnomad OTH AF: 0.705

GnomAD4 exome AF: 0.635 AC: 540312 AN: 851008 Hom.: 179123 AF XY: 0.642 AC XY: 284368 AN XY: 442876

African (AFR) AF: 0.936 AC: 19812 AN: 21174

American (AMR) AF: 0.769 AC: 28081 AN: 36494

Ashkenazi Jewish (ASJ) AF: 0.656 AC: 13927 AN: 21220

East Asian (EAS) AF: 0.999 AC: 35140 AN: 35162

South Asian (SAS) AF: 0.860 AC: 58283 AN: 67768

European-Finnish (FIN) AF: 0.516 AC: 22036 AN: 42730

Middle Eastern (MID) AF: 0.791 AC: 3297 AN: 4166

European-Non Finnish (NFE) AF: 0.572 AC: 333168 AN: 582524

Other (OTH) AF: 0.668 AC: 26568 AN: 39770

GnomAD4 genome AF: 0.708 AC: 107683 AN: 152088 Hom.: 40424 Cov.: 31 AF XY: 0.710 AC XY: 52751 AN XY: 74336

African (AFR) AF: 0.925 AC: 38409 AN: 41530

American (AMR) AF: 0.754 AC: 11522 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.658 AC: 2283 AN: 3470

East Asian (EAS) AF: 0.998 AC: 5169 AN: 5180

South Asian (SAS) AF: 0.871 AC: 4189 AN: 4812

European-Finnish (FIN) AF: 0.504 AC: 5313 AN: 10552

Middle Eastern (MID) AF: 0.769 AC: 226 AN: 294

European-Non Finnish (NFE) AF: 0.567 AC: 38525 AN: 67942

Other (OTH) AF: 0.709 AC: 1501 AN: 2116

Alfa AF: 0.630 Hom.: 43771

Bravo AF: 0.734

Asia WGS AF: 0.926 AC: 3218 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	2.8
DANN	Benign	0.28
PhyloP100		0.026
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3731566; hg19: chr10-111886089;