rs41291886

Positions:

chr10-110112885-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000356080.9(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
ENST00000356080.9 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 3.08

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 25 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADD3	NM_016824.5 linkuse as main transcript	c.304T>C	p.Ser102Pro	missense_variant	3/15	ENST00000356080.9	NP_058432.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADD3	ENST00000356080.9 linkuse as main transcript	c.304T>C	p.Ser102Pro	missense_variant	3/15	1	NM_016824.5	ENSP00000348381	A1	Q9UEY8-1

Frequencies

GnomAD3 genomes

AF:

0.0112

AC:

1711

AN:

152208

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.00316

AC:

794

AN:

251108

Hom.:

AF XY:

0.00229

AC XY:

311

AN XY:

135718

show subpopulations

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 SAS exome

AF:

0.000131

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.:

Cov.:

AF XY:

0.00122

AC XY:

889

AN XY:

727126

show subpopulations

Gnomad4 AFR exome

AF:

0.0420

Gnomad4 AMR exome

AF:

0.00289

Gnomad4 ASJ exome

AF:

0.000919

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000290

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000161

Gnomad4 OTH exome

AF:

0.00313

GnomAD4 genome

AF:

0.0113

AC:

1715

AN:

152326

Hom.:

Cov.:

AF XY:

0.0105

AC XY:

784

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.0387

Gnomad4 AMR

AF:

0.00503

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.00615

Alfa

AF:

0.00273

Hom.:

Bravo

AF:

0.0136

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.0363

AC:

160

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00390

AC:

474

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000533

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 30, 2016	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.49

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

.;T;.

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

.;D;D

MetaRNN

Benign

0.0044

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.0

M;M;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-1.5

N;N;N

REVEL

Benign

0.15

Sift

Benign

0.15

T;T;T

Sift4G

Benign

0.094

T;T;T

Polyphen

0.98

D;P;D

Vest4

0.83

MVP

0.17

MPC

0.37

ClinPred

0.016

GERP RS

5.8

Varity_R

0.24

gMVP

0.87

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over