4-2875990-C-G

Variant names:

• chr4-2875990-C-G
• NM_001354761.2:c.75C>G
• ADD1 p.Phe25Leu

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001354761.2(ADD1):​c.75C>G​(p.Phe25Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. F25F) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADD1 NM_001354761.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.503
• Publications: 0 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21762264).

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.75C>G	p.Phe25Leu	missense	Exon 2 of 16	NP_001341690.1	A0A804HL01
	ADD1	NM_001354756.2		c.75C>G	p.Phe25Leu	missense	Exon 2 of 16	NP_001341685.1
	ADD1	NM_014189.4		c.75C>G	p.Phe25Leu	missense	Exon 2 of 15	NP_054908.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADD1	ENST00000683351.1	MANE Select	c.75C>G	p.Phe25Leu	missense	Exon 2 of 16	ENSP00000508142.1	A0A804HL01
	ADD1	ENST00000355842.7	TSL:1	c.75C>G	p.Phe25Leu	missense	Exon 3 of 18	ENSP00000348100.3	P35611-4
	ADD1	ENST00000398123.6	TSL:1	c.75C>G	p.Phe25Leu	missense	Exon 1 of 15	ENSP00000381191.2	P35611-6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.060	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.22	N
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		-0.50
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.11
Sift	Uncertain	0.016	D
Sift4G	Benign	0.093	T
PromoterAI		-0.041	Neutral
Varity_R		0.17
gMVP		0.26
Mutation Taster		=64/36	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr4-2877717;