Variant 4-2875995-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001354761.2(ADD1):c.80G>T(p.Arg27Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,782 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

ADD1
NM_001354761.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.86

Variant links:

Genes affected

ADD1 (HGNC:243): (adducin 1) Adducins are a family of cytoskeletal proteins encoded by three genes (alpha, beta, and gamma). Adducin acts as a heterodimer of the related alpha, beta, or gamma subunits. The protein encoded by this gene represents the alpha subunit. Alpha- and beta-adducin include a protease-resistant N-terminal region and a protease-sensitive, hydrophilic C-terminal region. Adducin binds with high affinity to Ca(2+)/calmodulin and is a substrate for protein kinases A and C. [provided by RefSeq, Aug 2017]

ADD1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.778

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADD1	NM_001354761.2 link	c.80G>T	p.Arg27Leu	missense_variant	2/16	ENST00000683351.1	NP_001341690.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADD1	ENST00000683351.1 link	c.80G>T	p.Arg27Leu	missense_variant	2/16		NM_001354761.2	ENSP00000508142.1		A0A804HL01

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251312

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135832

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000869

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461782

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727196

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 20, 2023

The c.80G>T (p.R27L) alteration is located in exon 2 (coding exon 1) of the ADD1 gene. This alteration results from a G to T substitution at nucleotide position 80, causing the arginine (R) at amino acid position 27 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Pathogenic

0.14

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.086

.;.;T;.;T;.;T;.;.;D

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D;D;D;D;D;D;D;.;D

M_CAP

Benign

0.036

MetaRNN

Pathogenic

0.78

D;D;D;D;D;D;D;D;D;D

MetaSVM

Benign

-0.63

MutationAssessor

Uncertain

2.4

M;M;.;.;.;.;.;M;M;M

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-4.4

D;D;D;D;D;N;D;D;D;D

REVEL

Uncertain

0.47

Sift

Uncertain

0.0020

D;D;D;D;D;T;D;D;D;D

Sift4G

Uncertain

0.025

D;D;D;D;D;D;D;D;D;D

Polyphen

0.99

D;.;.;.;.;.;D;.;.;D

Vest4

0.87

MutPred

0.39

Gain of glycosylation at Y24 (P = 0.0021);Gain of glycosylation at Y24 (P = 0.0021);Gain of glycosylation at Y24 (P = 0.0021);Gain of glycosylation at Y24 (P = 0.0021);Gain of glycosylation at Y24 (P = 0.0021);Gain of glycosylation at Y24 (P = 0.0021);Gain of glycosylation at Y24 (P = 0.0021);Gain of glycosylation at Y24 (P = 0.0021);Gain of glycosylation at Y24 (P = 0.0021);Gain of glycosylation at Y24 (P = 0.0021);

MVP

0.75

MPC

0.83

ClinPred

0.98

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.59

gMVP

0.57

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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