Variant 4-2898497-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001354761.2(ADD1):c.950A>C(p.Tyr317Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000131 in 152,194 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Consequence

ADD1
NM_001354761.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.31

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 made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADD1	NM_001354761.2 linkuse as main transcript	c.950A>C	p.Tyr317Ser	missense_variant	8/16	ENST00000683351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADD1	ENST00000683351.1 linkuse as main transcript	c.950A>C	p.Tyr317Ser	missense_variant	8/16		NM_001354761.2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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

AF:

0.0000131

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

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

Feb 13, 2024

The c.950A>C (p.Y317S) alteration is located in exon 8 (coding exon 7) of the ADD1 gene. This alteration results from a A to C substitution at nucleotide position 950, causing the tyrosine (Y) at amino acid position 317 to be replaced by a serine (S). 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

Benign

0.17

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.040

Cadd

Uncertain

Dann

Uncertain

0.99

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.85

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

M_CAP

Benign

0.035

MetaRNN

Uncertain

0.57

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.2

L;L;.;.;.;L;L;L

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.72

PROVEAN

Uncertain

-3.6

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

REVEL

Benign

0.28

Sift

Benign

0.043

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

Sift4G

Benign

0.26

T;T;T;T;T;T;T;T

Polyphen

0.23

B;.;.;P;P;.;.;P

Vest4

0.66

MutPred

0.47

Gain of disorder (P = 0.0319);Gain of disorder (P = 0.0319);Gain of disorder (P = 0.0319);Gain of disorder (P = 0.0319);Gain of disorder (P = 0.0319);Gain of disorder (P = 0.0319);Gain of disorder (P = 0.0319);Gain of disorder (P = 0.0319);

MVP

0.69

MPC

0.95

ClinPred

0.96

GERP RS

5.7

Varity_R

0.61

gMVP

0.90

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

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