chr2-239053470-C-T

Position:

chr2-239053470-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

The NM_001378414.1(HDAC4):c.3220G>A(p.Ala1074Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000567 in 1,612,938 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00043 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00058 ( 2 hom. )

Consequence

HDAC4
NM_001378414.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 0.999

Variant links:

Genes affected

HDAC4 (HGNC:14063): (histone deacetylase 4) Histones play a critical role in transcriptional regulation, cell cycle progression, and developmental events. Histone acetylation/deacetylation alters chromosome structure and affects transcription factor access to DNA. The protein encoded by this gene belongs to class II of the histone deacetylase/acuc/apha family. It possesses histone deacetylase activity and represses transcription when tethered to a promoter. This protein does not bind DNA directly, but through transcription factors MEF2C and MEF2D. It seems to interact in a multiprotein complex with RbAp48 and HDAC3. [provided by RefSeq, Jul 2008]

HDAC4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), HDAC4. . Gene score misZ 2.926 (greater than the threshold 3.09). Trascript score misZ 3.7504 (greater than threshold 3.09). GenCC has associacion of gene with neurodevelopmental disorder with central hypotonia and dysmorphic facies, 2q37 microdeletion syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.009914041).

BP6

Variant 2-239053470-C-T is Benign according to our data. Variant chr2-239053470-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 374654.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000433 (66/152342) while in subpopulation SAS AF= 0.000828 (4/4832). AF 95% confidence interval is 0.000431. There are 0 homozygotes in gnomad4. There are 35 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 66 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HDAC4	NM_001378414.1 linkuse as main transcript	c.3220G>A	p.Ala1074Thr	missense_variant	26/27	ENST00000543185.6	NP_001365343.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HDAC4	ENST00000543185.6 linkuse as main transcript	c.3220G>A	p.Ala1074Thr	missense_variant	26/27	5	NM_001378414.1	ENSP00000440481	A1
HDAC4	ENST00000345617.7 linkuse as main transcript	c.3205G>A	p.Ala1069Thr	missense_variant	26/27	1		ENSP00000264606	P4	P56524-1
HDAC4	ENST00000430200.1 linkuse as main transcript	c.478G>A	p.Ala160Thr	missense_variant	3/4	3		ENSP00000410551
HDAC4	ENST00000690129.1 linkuse as main transcript	n.1234G>A		non_coding_transcript_exon_variant	9/10

Frequencies

GnomAD3 genomes

AF:

0.000434

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000827

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000573

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000564

AC:

141

AN:

249986

Hom.:

AF XY:

0.000576

AC XY:

AN XY:

135318

show subpopulations

Gnomad AFR exome

AF:

0.000433

Gnomad AMR exome

AF:

0.000985

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000819

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.000577

Gnomad OTH exome

AF:

0.00148

GnomAD4 exome

AF:

0.000581

AC:

848

AN:

1460596

Hom.:

Cov.:

AF XY:

0.000603

AC XY:

438

AN XY:

726528

show subpopulations

Gnomad4 AFR exome

AF:

0.000508

Gnomad4 AMR exome

AF:

0.00103

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000963

Gnomad4 FIN exome

AF:

0.0000756

Gnomad4 NFE exome

AF:

0.000597

Gnomad4 OTH exome

AF:

0.000514

GnomAD4 genome

AF:

0.000433

AC:

AN:

152342

Hom.:

Cov.:

AF XY:

0.000470

AC XY:

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.000337

Gnomad4 AMR

AF:

0.000457

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000828

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000573

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000562

Hom.:

Bravo

AF:

0.000502

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000568

AC:

EpiCase

AF:

0.000872

EpiControl

AF:

0.00113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 02, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.54

D;.

Eigen

Benign

-0.91

Eigen_PC

Benign

-0.91

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.68

T;T

M_CAP

Benign

0.035

MetaRNN

Benign

0.0099

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

L;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.1

N;.

REVEL

Benign

0.080

Sift

Benign

0.11

T;.

Sift4G

Benign

0.46

T;T

Polyphen

0.0

B;.

Vest4

0.18

MVP

0.53

MPC

0.83

ClinPred

0.015

GERP RS

1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.036

gMVP

0.23

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