rs41291886

Variant names:

• chr10-110112885-T-C
• rs41291886
• NM_016824.5:c.304T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_016824.5(ADD3):​c.304T>C​(p.Ser102Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00229 in 1,613,978 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (25 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (30 hom.)
• Consequence: ADD3 NM_016824.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.08
• Publications: 5 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0044383705).
• BP6: Variant 10-110112885-T-C is Benign according to our data. Variant chr10-110112885-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 376951.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0113 (1715/152326) while in subpopulation AFR AF = 0.0387 (1607/41578). AF 95% confidence interval is 0.0371. There are 25 homozygotes in GnomAd4. There are 784 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 25 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADD3	NM_016824.5	MANE Select	c.304T>C	p.Ser102Pro	missense	Exon 3 of 15	NP_058432.1	Q9UEY8-1
	ADD3	NM_001320591.2		c.304T>C	p.Ser102Pro	missense	Exon 4 of 16	NP_001307520.1	Q9UEY8-1
	ADD3	NM_001320592.2		c.304T>C	p.Ser102Pro	missense	Exon 3 of 15	NP_001307521.1	Q9UEY8-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADD3	ENST00000356080.9	TSL:1 MANE Select	c.304T>C	p.Ser102Pro	missense	Exon 3 of 15	ENSP00000348381.4	Q9UEY8-1
	ADD3	ENST00000277900.12	TSL:1	c.304T>C	p.Ser102Pro	missense	Exon 3 of 14	ENSP00000277900.8	Q9UEY8-2
	ADD3	ENST00000360162.7	TSL:1	c.304T>C	p.Ser102Pro	missense	Exon 3 of 14	ENSP00000353286.3	Q9UEY8-2

Frequencies

GnomAD3 genomes AF: 0.0112 AC: 1711 AN: 152208 Hom.: 25 Cov.: 32

Gnomad AFR AF: 0.0387

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00504

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00621

GnomAD2 exomes AF: 0.00316 AC: 794 AN: 251108 AF XY: 0.00229

Gnomad AFR exome AF: 0.0400

Gnomad AMR exome AF: 0.00241

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000326

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00136 AC: 1987 AN: 1461652 Hom.: 30 Cov.: 31 AF XY: 0.00122 AC XY: 889 AN XY: 727126

African (AFR) AF: 0.0420 AC: 1406 AN: 33462

American (AMR) AF: 0.00289 AC: 129 AN: 44650

Ashkenazi Jewish (ASJ) AF: 0.000919 AC: 24 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.000290 AC: 25 AN: 86214

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00607 AC: 35 AN: 5766

European-Non Finnish (NFE) AF: 0.000161 AC: 179 AN: 1111942

Other (OTH) AF: 0.00313 AC: 189 AN: 60388

GnomAD4 genome AF: 0.0113 AC: 1715 AN: 152326 Hom.: 25 Cov.: 32 AF XY: 0.0105 AC XY: 784 AN XY: 74488

African (AFR) AF: 0.0387 AC: 1607 AN: 41578

American (AMR) AF: 0.00503 AC: 77 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68028

Other (OTH) AF: 0.00615 AC: 13 AN: 2114

Alfa AF: 0.00496 Hom.: 36

Bravo AF: 0.0136

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0363 AC: 160

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00390 AC: 474

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000533

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.49
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0044	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		3.1
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.15
Sift	Benign	0.15	T
Sift4G	Benign	0.094	T
Polyphen		0.98	D
Vest4		0.83
MVP		0.17
MPC		0.37
ClinPred		0.016	T
GERP RS		5.8
Varity_R		0.24
gMVP		0.87
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs41291886; hg19: chr10-111872643;