Genetic Variant NM_014913.4:c.144T>G (chr18-80133138-T-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_014913.4(ADNP2):c.144T>G(p.Phe48Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,460,384 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

ADNP2
NM_014913.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0630

Variant links:

Genes affected

ADNP2 (HGNC:23803): (ADNP homeobox 2) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific. Predicted to be involved in several processes, including cellular response to oxidative stress; cellular response to retinoic acid; and positive regulation of cell growth. Predicted to be part of chromatin. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ADNP2 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=0.12914664).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADNP2	NM_014913.4 link	c.144T>G	p.Phe48Leu	missense_variant	Exon 3 of 4	ENST00000262198.9	NP_055728.1	Q6IQ32A0A024R377

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADNP2	ENST00000262198.9 link	c.144T>G	p.Phe48Leu	missense_variant	Exon 3 of 4	1	NM_014913.4	ENSP00000262198.3		Q6IQ32

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000800

AC:

AN:

250098

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135140

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000548

AC:

AN:

1460384

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

726464

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:

0.00000720

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.144T>G (p.F48L) alteration is located in exon 3 (coding exon 2) of the ADNP2 gene. This alteration results from a T to G substitution at nucleotide position 144, causing the phenylalanine (F) at amino acid position 48 to be replaced by a leucine (L). 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

Pathogenic

0.85

BayesDel_addAF

Benign

-0.096

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Benign

0.88

DEOGEN2

Benign

0.096

T;.;T

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.61

LIST_S2

Benign

0.66

T;T;T

M_CAP

Benign

0.035

MetaRNN

Benign

0.13

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.9

L;.;.

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-2.4

N;D;D

REVEL

Benign

0.075

Sift

Benign

0.28

T;T;T

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

0.011

B;.;.

Vest4

0.56

MutPred

0.35

Gain of catalytic residue at F48 (P = 0.0571);.;Gain of catalytic residue at F48 (P = 0.0571);

MVP

0.79

MPC

0.23

ClinPred

0.10

GERP RS

0.95

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.13

gMVP

0.68

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over