Genetic Variant ADD1:p.Val198Phe (chr4-2894582-G-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_001354761.2(ADD1):c.592G>T(p.Val198Phe) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 32)

Failed GnomAD Quality Control

Consequence

ADD1
NM_001354761.2 missense, splice_region

Scores

Splicing: ADA: 0.9255

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.87

Publications

0 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.836

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001354761.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ADD1	NM_001354761.2	MANE Select	c.592G>T	p.Val198Phe	missense splice_region	Exon 6 of 16	NP_001341690.1	A0A804HL01
ADD1	NM_001354756.2		c.592G>T	p.Val198Phe	missense splice_region	Exon 6 of 16	NP_001341685.1
ADD1	NM_014189.4		c.592G>T	p.Val198Phe	missense splice_region	Exon 6 of 15	NP_054908.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ADD1	ENST00000683351.1	MANE Select	c.592G>T	p.Val198Phe	missense splice_region	Exon 6 of 16	ENSP00000508142.1	A0A804HL01
ADD1	ENST00000355842.7	TSL:1	c.592G>T	p.Val198Phe	missense splice_region	Exon 7 of 18	ENSP00000348100.3	P35611-4
ADD1	ENST00000398123.6	TSL:1	c.592G>T	p.Val198Phe	missense splice_region	Exon 5 of 15	ENSP00000381191.2	P35611-6

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

151562

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

151562

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73966

African (AFR)

AF:

0.00

AC:

AN:

41292

American (AMR)

AF:

0.00

AC:

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10338

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67892

Other (OTH)

AF:

0.00

AC:

AN:

2082

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.79

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.14

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.97

M_CAP

Uncertain

0.099

MetaRNN

Pathogenic

0.84

MetaSVM

Benign

-0.53

MutationAssessor

Pathogenic

3.2

PhyloP100

6.9

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-4.3

REVEL

Uncertain

0.43

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0050

Polyphen

0.95

Vest4

0.91

MutPred

0.74

Loss of stability (P = 0.0591)

MVP

0.72

MPC

0.73

ClinPred

1.0

GERP RS

4.9

Varity_R

0.69

gMVP

0.97

Mutation Taster

=48/52

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.93

dbscSNV1_RF

Pathogenic

0.76

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over