rs4971

Variant names:

• chr4-2898250-T-A
• rs4971
• NM_001354761.2:c.808T>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001354761.2(ADD1):​c.808T>A​(p.Tyr270Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADD1 NM_001354761.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.95
• Publications: 8 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.86

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.808T>A	p.Tyr270Asn	missense	Exon 7 of 16	NP_001341690.1
	ADD1	NM_001354756.2		c.808T>A	p.Tyr270Asn	missense	Exon 7 of 16	NP_001341685.1
	ADD1	NM_014189.4		c.808T>A	p.Tyr270Asn	missense	Exon 7 of 15	NP_054908.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADD1	ENST00000683351.1	MANE Select	c.808T>A	p.Tyr270Asn	missense	Exon 7 of 16	ENSP00000508142.1
	ADD1	ENST00000355842.7	TSL:1	c.808T>A	p.Tyr270Asn	missense	Exon 8 of 18	ENSP00000348100.3
	ADD1	ENST00000398123.6	TSL:1	c.808T>A	p.Tyr270Asn	missense	Exon 6 of 15	ENSP00000381191.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.088	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Uncertain	-0.097	T
MutationAssessor	Pathogenic	4.1	H
PhyloP100		8.0
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-6.1	D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.030	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.39		Gain of glycosylation at Y273 (P = 0.0237)
MVP		0.61
MPC		1.1
ClinPred		1.0	D
GERP RS		5.9
PromoterAI		-0.0026	Neutral
Varity_R		0.79
gMVP		0.93
Mutation Taster		=34/66	disease causing

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

Other links and lift over

dbSNP: rs4971; hg19: chr4-2899977;