chr2-239053442-G-A

Variant names:

• chr2-239053442-G-A
• rs200713014
• NM_001378414.1:c.3230+18C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001378414.1(HDAC4):​c.3230+18C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00166 in 1,610,110 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (5 hom.)
• Consequence: HDAC4 NM_001378414.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.178
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with central hypotonia and dysmorphic facies

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• 2q37 microdeletion syndrome

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 2-239053442-G-A is Benign according to our data. Variant chr2-239053442-G-A is described in ClinVar as Benign. ClinVar VariationId is 2887533.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00109 (166/152326) while in subpopulation NFE AF = 0.00193 (131/68024). AF 95% confidence interval is 0.00166. There are 0 homozygotes in GnomAd4. There are 74 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 166 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378414.1. 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
	HDAC4	NM_001378414.1	MANE Select	c.3230+18C>T		intron	N/A	NP_001365343.1	A0A7I2SVS4
	HDAC4	NM_001378415.1		c.3230+18C>T		intron	N/A	NP_001365344.1	A0A7I2SVS4
	HDAC4	NM_001378416.1		c.3215+18C>T		intron	N/A	NP_001365345.1	P56524-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HDAC4	ENST00000543185.6	TSL:5 MANE Select	c.3230+18C>T		intron	N/A	ENSP00000440481.3	A0A7I2SVS4
	HDAC4	ENST00000345617.7	TSL:1	c.3215+18C>T		intron	N/A	ENSP00000264606.3	P56524-1
	HDAC4	ENST00000896768.1		c.3230+18C>T		intron	N/A	ENSP00000566827.1

Frequencies

GnomAD3 genomes AF: 0.00109 AC: 166 AN: 152208 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000376

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00193

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00110 AC: 272 AN: 248274 AF XY: 0.000974

Gnomad AFR exome AF: 0.000872

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.000807

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000749

Gnomad NFE exome AF: 0.00195

Gnomad OTH exome AF: 0.000827

GnomAD4 exome AF: 0.00172 AC: 2503 AN: 1457784 Hom.: 5 Cov.: 32 AF XY: 0.00161 AC XY: 1168 AN XY: 724678

African (AFR) AF: 0.000718 AC: 24 AN: 33424

American (AMR) AF: 0.000292 AC: 13 AN: 44566

Ashkenazi Jewish (ASJ) AF: 0.00119 AC: 31 AN: 25988

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39606

South Asian (SAS) AF: 0.0000349 AC: 3 AN: 85996

European-Finnish (FIN) AF: 0.000761 AC: 40 AN: 52568

Middle Eastern (MID) AF: 0.000177 AC: 1 AN: 5648

European-Non Finnish (NFE) AF: 0.00209 AC: 2318 AN: 1109740

Other (OTH) AF: 0.00118 AC: 71 AN: 60248

GnomAD4 genome AF: 0.00109 AC: 166 AN: 152326 Hom.: 0 Cov.: 33 AF XY: 0.000994 AC XY: 74 AN XY: 74484

African (AFR) AF: 0.000577 AC: 24 AN: 41574

American (AMR) AF: 0.000327 AC: 5 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.000376 AC: 4 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00193 AC: 131 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.00133 Hom.: 0

Bravo AF: 0.00107

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.29
DANN	Benign	0.59
PhyloP100		-0.18
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs200713014; hg19: chr2-239975138;