rs4962

chr4-2908528-A-T

Variant summary

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

The NM_001354761.2(ADD1):c.1622A>T(p.Asn541Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ADD1 NM_001354761.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.84

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]

ACMG classification

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	c.1622A>T	p.Asn541Ile	missense_variant	12/16	ENST00000683351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADD1	ENST00000683351.1	c.1622A>T	p.Asn541Ile	missense_variant	12/16		NM_001354761.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
Cadd	Pathogenic	26
Dann	Uncertain	0.99
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;.;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.74	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.80	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-6.5	D;D;D;D;D;D;D;D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0080	D;D;D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.;D;.
Vest4		0.81
MutPred		0.24		.;.;Loss of disorder (P = 0.0212);.;Loss of disorder (P = 0.0212);.;Loss of disorder (P = 0.0212);.;
MVP		0.68
MPC		0.95
ClinPred		0.99	D
GERP RS		5.9
Varity_R		0.80
gMVP		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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

Other links and lift over

dbSNP: rs4962; hg19: chr4-2910255;