Genetic Variant NM_001354761.2:c.93C>G (chr4-2876008-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001354761.2(ADD1):c.93C>G(p.Asn31Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,818 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ADD1
NM_001354761.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.06

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.23444349).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADD1	NM_001354761.2 link	c.93C>G	p.Asn31Lys	missense_variant	Exon 2 of 16	ENST00000683351.1	NP_001341690.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADD1	ENST00000683351.1 link	c.93C>G	p.Asn31Lys	missense_variant	Exon 2 of 16		NM_001354761.2	ENSP00000508142.1		A0A804HL01

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461818

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727208

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 08, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.93C>G (p.N31K) alteration is located in exon 2 (coding exon 1) of the ADD1 gene. This alteration results from a C to G substitution at nucleotide position 93, causing the asparagine (N) at amino acid position 31 to be replaced by a lysine (K). 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

Uncertain

0.48

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.072

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

Eigen

Benign

-0.074

Eigen_PC

Benign

-0.021

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.90

D;D;D;D;D;D;D;D;.;D

M_CAP

Benign

0.013

MetaRNN

Benign

0.23

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

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

PrimateAI

Pathogenic

0.81

PROVEAN

Uncertain

-2.6

D;D;D;D;D;N;D;D;D;D

REVEL

Benign

0.065

Sift

Uncertain

0.0050

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

Sift4G

Uncertain

0.031

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

Polyphen

0.16

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

Vest4

0.30

MutPred

0.25

Gain of glycosylation at Y35 (P = 0.0016);Gain of glycosylation at Y35 (P = 0.0016);Gain of glycosylation at Y35 (P = 0.0016);Gain of glycosylation at Y35 (P = 0.0016);Gain of glycosylation at Y35 (P = 0.0016);Gain of glycosylation at Y35 (P = 0.0016);Gain of glycosylation at Y35 (P = 0.0016);Gain of glycosylation at Y35 (P = 0.0016);Gain of glycosylation at Y35 (P = 0.0016);Gain of glycosylation at Y35 (P = 0.0016);

MVP

0.45

MPC

0.58

ClinPred

0.95

GERP RS

2.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.42

gMVP

0.21

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over