Genetic Variant ADD3-AS1:n.335+8041C>G (chr10-109997916-G-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000369655.4(ADD3-AS1):n.335+8041C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.455 in 151,988 control chromosomes in the GnomAD database, including 19,264 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 0.45 ( 19264 hom., cov: 31)

Consequence

ADD3-AS1
ENST00000369655.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.641

Publications

7 publications found

Variant links:

Genes affected

ADD3-AS1 (HGNC:48682): (ADD3 antisense RNA 1)

ADD3-AS1 links:

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

ADD3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.633 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	Protein	UniProt
ADD3	NM_001320591.2 link	c.-218+1470G>C	intron_variant	Intron 1 of 15	NP_001307520.1	Q9UEY8-1Q5VU08Q53FL4
ADD3-AS1	NR_038943.1 link	n.326+8041C>G	intron_variant	Intron 2 of 4
ADD3	XM_024447799.2 link	c.-30+1470G>C	intron_variant	Intron 1 of 14	XP_024303567.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL
ADD3-AS1	ENST00000369655.4 link	n.335+8041C>G	intron_variant	Intron 2 of 5	1
ADD3	ENST00000468251.5 link	n.79+1470G>C	intron_variant	Intron 1 of 5	5
ADD3-AS1	ENST00000625954.4 link	n.335+8041C>G	intron_variant	Intron 2 of 4	3

Frequencies

GnomAD3 genomes

AF:

0.455

AC:

69133

AN:

151868

Hom.:

19275

Cov.:

show subpopulations

Gnomad AFR

AF:

0.159

Gnomad AMI

AF:

0.608

Gnomad AMR

AF:

0.391

Gnomad ASJ

AF:

0.578

Gnomad EAS

AF:

0.222

Gnomad SAS

AF:

0.289

Gnomad FIN

AF:

0.662

Gnomad MID

AF:

0.525

Gnomad NFE

AF:

0.638

Gnomad OTH

AF:

0.477

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.455

AC:

69103

AN:

151988

Hom.:

19264

Cov.:

AF XY:

0.452

AC XY:

33553

AN XY:

74284

show subpopulations

African (AFR)

AF:

0.158

AC:

6569

AN:

41446

American (AMR)

AF:

0.390

AC:

5952

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.578

AC:

2008

AN:

3472

East Asian (EAS)

AF:

0.222

AC:

1150

AN:

5178

South Asian (SAS)

AF:

0.289

AC:

1390

AN:

4810

European-Finnish (FIN)

AF:

0.662

AC:

6985

AN:

10556

Middle Eastern (MID)

AF:

0.514

AC:

151

AN:

294

European-Non Finnish (NFE)

AF:

0.638

AC:

43356

AN:

67956

Other (OTH)

AF:

0.470

AC:

991

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1580

3160

4739

6319

7899

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

602

1204

1806

2408

3010

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.421

Hom.:

1464

Bravo

AF:

0.424

Asia WGS

AF:

0.219

AC:

762

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

1.4

(source)

DANN

Benign

0.42

PhyloP100

0.64

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over