rs73000144

Positions:

• chr2-239139704-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001378414.1(HDAC4):​c.958G>A​(p.Val320Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00379 in 1,614,018 control chromosomes in the GnomAD database, including 19 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V320A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0032 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0039 (16 hom.)
• Consequence: HDAC4 NM_001378414.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.56

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, HDAC4
• BP4: Computational evidence support a benign effect (MetaRNN=0.0073234737).
• BP6: Variant 2-239139704-C-T is Benign according to our data. Variant chr2-239139704-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 284720.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-239139704-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00319 (486/152354) while in subpopulation NFE AF= 0.00522 (355/68038). AF 95% confidence interval is 0.00477. There are 3 homozygotes in gnomad4. There are 219 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 486 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HDAC4	NM_001378414.1	c.958G>A	p.Val320Ile	missense_variant	9/27	ENST00000543185.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HDAC4	ENST00000543185.6	c.958G>A	p.Val320Ile	missense_variant	9/27	5	NM_001378414.1	A1

Frequencies

GnomAD3 genomes AF: 0.00319 AC: 485 AN: 152236 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000989

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.00333

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.000376

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00520

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00304 AC: 761 AN: 250556 Hom.: 2 AF XY: 0.00326 AC XY: 442 AN XY: 135512

Gnomad AFR exome AF: 0.000556

Gnomad AMR exome AF: 0.00217

Gnomad ASJ exome AF: 0.00368

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000555

Gnomad FIN exome AF: 0.000693

Gnomad NFE exome AF: 0.00517

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00385 AC: 5633 AN: 1461664 Hom.: 16 Cov.: 31 AF XY: 0.00388 AC XY: 2821 AN XY: 727140

Gnomad4 AFR exome AF: 0.000687

Gnomad4 AMR exome AF: 0.00255

Gnomad4 ASJ exome AF: 0.00344

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000626

Gnomad4 FIN exome AF: 0.000675

Gnomad4 NFE exome AF: 0.00458

Gnomad4 OTH exome AF: 0.00349

GnomAD4 genome AF: 0.00319 AC: 486 AN: 152354 Hom.: 3 Cov.: 33 AF XY: 0.00294 AC XY: 219 AN XY: 74506

Gnomad4 AFR AF: 0.000986

Gnomad4 AMR AF: 0.00333

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.000376

Gnomad4 NFE AF: 0.00522

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00425 Hom.: 2

Bravo AF: 0.00336

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00453 AC: 39

ExAC AF: 0.00304 AC: 369

Asia WGS AF: 0.000289 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	This variant is associated with the following publications: (PMID: 25335771) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 15, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	HDAC4: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Nov 24, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	12
DANN	Uncertain	0.99
DEOGEN2	Benign	0.38	T;.
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.80	T;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.0073	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.25	N;.
MutationTaster	Benign	1.0	D;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.36	N;N
REVEL	Benign	0.028
Sift	Benign	0.47	T;T
Sift4G	Benign	0.25	T;T
Polyphen		0.0020	B;.
Vest4		0.26
MVP		0.45
MPC		0.34
ClinPred		0.0054	T
GERP RS		2.8
Varity_R		0.037
gMVP		0.12

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

Other links and lift over

dbSNP: rs73000144; hg19: chr2-240061400; COSMIC: COSV61862015;