rs7090030

Variant names:

• chr10-110100915-T-G
• rs7090030
• NM_016824.5:c.195+67T>G

Variant summary

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

The NM_016824.5(ADD3):​c.195+67T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0305 in 1,427,598 control chromosomes in the GnomAD database, including 8,989 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 0.14 (5016 hom., cov: 31)
  • Exomes 𝑓: 0.017 (3973 hom.)
• Consequence: ADD3 NM_016824.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0100
• Publications: 2 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=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.481 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADD3	NM_016824.5	c.195+67T>G		intron_variant	Intron 2 of 14	ENST00000356080.9	NP_058432.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADD3	ENST00000356080.9	c.195+67T>G		intron_variant	Intron 2 of 14	1	NM_016824.5	ENSP00000348381.4

Frequencies

GnomAD3 genomes AF: 0.142 AC: 21646 AN: 151964 Hom.: 4991 Cov.: 31

Gnomad AFR AF: 0.486

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0595

Gnomad ASJ AF: 0.00865

Gnomad EAS AF: 0.00540

Gnomad SAS AF: 0.0216

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.00375

Gnomad OTH AF: 0.112

GnomAD4 exome AF: 0.0171 AC: 21860 AN: 1275516 Hom.: 3973 AF XY: 0.0162 AC XY: 10117 AN XY: 624970

African (AFR) AF: 0.520 AC: 14003 AN: 26920

American (AMR) AF: 0.0392 AC: 915 AN: 23314

Ashkenazi Jewish (ASJ) AF: 0.0110 AC: 209 AN: 18936

East Asian (EAS) AF: 0.00493 AC: 166 AN: 33666

South Asian (SAS) AF: 0.0233 AC: 1386 AN: 59606

European-Finnish (FIN) AF: 0.000210 AC: 10 AN: 47550

Middle Eastern (MID) AF: 0.0567 AC: 211 AN: 3724

European-Non Finnish (NFE) AF: 0.00293 AC: 2958 AN: 1009174

Other (OTH) AF: 0.0380 AC: 2002 AN: 52626

GnomAD4 genome AF: 0.143 AC: 21718 AN: 152082 Hom.: 5016 Cov.: 31 AF XY: 0.138 AC XY: 10277 AN XY: 74358

African (AFR) AF: 0.486 AC: 20150 AN: 41426

American (AMR) AF: 0.0593 AC: 905 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00865 AC: 30 AN: 3468

East Asian (EAS) AF: 0.00541 AC: 28 AN: 5172

South Asian (SAS) AF: 0.0205 AC: 99 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.00375 AC: 255 AN: 68004

Other (OTH) AF: 0.111 AC: 234 AN: 2116

Alfa AF: 0.153 Hom.: 605

Bravo AF: 0.163

Asia WGS AF: 0.0430 AC: 151 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.8
DANN	Benign	0.74
PhyloP100		-0.010
Mutation Taster		=100/0	polymorphism (auto)

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: rs7090030; hg19: chr10-111860673;