NM_016824.5:c.1608+1869C>T

Variant names:

• chr10-110128372-C-T
• rs11194995
• NM_016824.5:c.1608+1869C>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.1608+1869C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.132 in 151,200 control chromosomes in the GnomAD database, including 4,244 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 0.13 (4244 hom., cov: 31)
• Consequence: ADD3 NM_016824.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.889
• 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=-0.86).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.443 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016824.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADD3	NM_016824.5	MANE Select	c.1608+1869C>T		intron	N/A	NP_058432.1
	ADD3	NM_001320591.2		c.1608+1869C>T		intron	N/A	NP_001307520.1
	ADD3	NM_001320592.2		c.1608+1869C>T		intron	N/A	NP_001307521.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADD3	ENST00000356080.9	TSL:1 MANE Select	c.1608+1869C>T		intron	N/A	ENSP00000348381.4
	ADD3	ENST00000277900.12	TSL:1	c.1608+1869C>T		intron	N/A	ENSP00000277900.8
	ADD3	ENST00000360162.7	TSL:1	c.1608+1869C>T		intron	N/A	ENSP00000353286.3

Frequencies

GnomAD3 genomes AF: 0.132 AC: 19948 AN: 151082 Hom.: 4220 Cov.: 31

Gnomad AFR AF: 0.448

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0575

Gnomad ASJ AF: 0.00895

Gnomad EAS AF: 0.00523

Gnomad SAS AF: 0.0219

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0510

Gnomad NFE AF: 0.00375

Gnomad OTH AF: 0.102

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

GnomAD4 genome AF: 0.132 AC: 20019 AN: 151200 Hom.: 4244 Cov.: 31 AF XY: 0.128 AC XY: 9474 AN XY: 73942

African (AFR) AF: 0.448 AC: 18503 AN: 41282

American (AMR) AF: 0.0573 AC: 873 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.00895 AC: 31 AN: 3462

East Asian (EAS) AF: 0.00524 AC: 27 AN: 5150

South Asian (SAS) AF: 0.0211 AC: 101 AN: 4794

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10286

Middle Eastern (MID) AF: 0.0582 AC: 17 AN: 292

European-Non Finnish (NFE) AF: 0.00375 AC: 254 AN: 67688

Other (OTH) AF: 0.101 AC: 213 AN: 2106

Alfa AF: 0.143 Hom.: 524

Bravo AF: 0.150

Asia WGS AF: 0.0410 AC: 144 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.29
DANN	Benign	0.74
PhyloP100		-0.89
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: rs11194995; hg19: chr10-111888130;