rs11194981

Variant names:

• chr10-110101296-T-C
• rs11194981
• NM_016824.5:c.195+448T>C

Your query was ambiguous. Multiple possible variants found:

• chr10-110101296-T-C
• chr10-110101296-T-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+448T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.282 in 151,824 control chromosomes in the GnomAD database, including 8,943 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 0.28 (8943 hom., cov: 31)
• Consequence: ADD3 NM_016824.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.639
• Publications: 6 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 = 0.571 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADD3	NM_016824.5	c.195+448T>C		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+448T>C		intron_variant	Intron 2 of 14	1	NM_016824.5	ENSP00000348381.4

Frequencies

GnomAD3 genomes AF: 0.282 AC: 42790 AN: 151706 Hom.: 8919 Cov.: 31

Gnomad AFR AF: 0.577

Gnomad AMI AF: 0.117

Gnomad AMR AF: 0.169

Gnomad ASJ AF: 0.168

Gnomad EAS AF: 0.406

Gnomad SAS AF: 0.394

Gnomad FIN AF: 0.0953

Gnomad MID AF: 0.191

Gnomad NFE AF: 0.149

Gnomad OTH AF: 0.260

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

GnomAD4 genome AF: 0.282 AC: 42868 AN: 151824 Hom.: 8943 Cov.: 31 AF XY: 0.281 AC XY: 20846 AN XY: 74248

African (AFR) AF: 0.577 AC: 23879 AN: 41352

American (AMR) AF: 0.169 AC: 2584 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.168 AC: 582 AN: 3460

East Asian (EAS) AF: 0.406 AC: 2088 AN: 5144

South Asian (SAS) AF: 0.392 AC: 1884 AN: 4802

European-Finnish (FIN) AF: 0.0953 AC: 1009 AN: 10588

Middle Eastern (MID) AF: 0.205 AC: 60 AN: 292

European-Non Finnish (NFE) AF: 0.149 AC: 10120 AN: 67888

Other (OTH) AF: 0.263 AC: 555 AN: 2114

Alfa AF: 0.247 Hom.: 1677

Bravo AF: 0.297

Asia WGS AF: 0.432 AC: 1501 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	1.4
DANN	Benign	0.31
PhyloP100		-0.64
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: rs11194981; hg19: chr10-111861054;