rs4962

Variant names:

• chr4-2908528-A-T
• rs4962
• NM_001354761.2:c.1622A>T

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 6 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADD1	NM_001354761.2	MANE Select	c.1622A>T	p.Asn541Ile	missense	Exon 12 of 16	NP_001341690.1	A0A804HL01
	ADD1	NM_001354756.2		c.1529A>T	p.Asn510Ile	missense	Exon 12 of 16	NP_001341685.1
	ADD1	NM_014189.4		c.1622A>T	p.Asn541Ile	missense	Exon 12 of 15	NP_054908.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADD1	ENST00000683351.1	MANE Select	c.1622A>T	p.Asn541Ile	missense	Exon 12 of 16	ENSP00000508142.1	A0A804HL01
	ADD1	ENST00000355842.7	TSL:1	c.1529A>T	p.Asn510Ile	missense	Exon 13 of 18	ENSP00000348100.3	P35611-4
	ADD1	ENST00000398123.6	TSL:1	c.1622A>T	p.Asn541Ile	missense	Exon 11 of 15	ENSP00000381191.2	P35611-6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.21	T
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.74	D
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		8.8
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-6.5	D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.81
MutPred		0.24		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
Mutation Taster		=53/47	polymorphism

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

Other links and lift over

dbSNP: rs4962; hg19: chr4-2910255;