5-141626120-A-G

Variant names:

• chr5-141626120-A-G
• rs2547547
• NM_003883.4:c.921-49T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003883.4(HDAC3):​c.921-49T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.113 in 1,605,160 control chromosomes in the GnomAD database, including 10,920 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.12 (1089 hom., cov: 31)
  • Exomes 𝑓: 0.11 (9831 hom.)
• Consequence: HDAC3 NM_003883.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0250
• Publications: 24 publications found

Genes affected

HDAC3 (HGNC:4854): (histone deacetylase 3) 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 the histone deacetylase/acuc/apha family. It has histone deacetylase activity and represses transcription when tethered to a promoter. It may participate in the regulation of transcription through its binding with the zinc-finger transcription factor YY1. This protein can also down-regulate p53 function and thus modulate cell growth and apoptosis. This gene is regarded as a potential tumor suppressor gene. [provided by RefSeq, Jul 2008]

HDAC3 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
• neurodevelopmental disorder

  Inheritance: AD Classification: MODERATE Submitted by: G2P

ENSG00000228737 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.143 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003883.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HDAC3	NM_003883.4	MANE Select	c.921-49T>C		intron	N/A	NP_003874.2
	HDAC3	NM_001355039.2		c.921-49T>C		intron	N/A	NP_001341968.1
	HDAC3	NM_001355040.2		c.462-49T>C		intron	N/A	NP_001341969.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HDAC3	ENST00000305264.8	TSL:1 MANE Select	c.921-49T>C		intron	N/A	ENSP00000302967.3
	HDAC3	ENST00000469550.6	TSL:1	n.994-49T>C		intron	N/A
	ENSG00000228737	ENST00000422040.2	TSL:3	n.260A>G		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes AF: 0.116 AC: 17653 AN: 151898 Hom.: 1089 Cov.: 31

Gnomad AFR AF: 0.114

Gnomad AMI AF: 0.0450

Gnomad AMR AF: 0.0759

Gnomad ASJ AF: 0.111

Gnomad EAS AF: 0.0903

Gnomad SAS AF: 0.153

Gnomad FIN AF: 0.175

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.118

Gnomad OTH AF: 0.128

GnomAD2 exomes AF: 0.113 AC: 28504 AN: 251368 AF XY: 0.117

Gnomad AFR exome AF: 0.113

Gnomad AMR exome AF: 0.0546

Gnomad ASJ exome AF: 0.103

Gnomad EAS exome AF: 0.0874

Gnomad FIN exome AF: 0.172

Gnomad NFE exome AF: 0.116

Gnomad OTH exome AF: 0.105

GnomAD4 exome AF: 0.112 AC: 163329 AN: 1453144 Hom.: 9831 Cov.: 28 AF XY: 0.114 AC XY: 82557 AN XY: 723592

African (AFR) AF: 0.111 AC: 3697 AN: 33314

American (AMR) AF: 0.0591 AC: 2644 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.102 AC: 2672 AN: 26100

East Asian (EAS) AF: 0.0747 AC: 2962 AN: 39654

South Asian (SAS) AF: 0.149 AC: 12789 AN: 86048

European-Finnish (FIN) AF: 0.172 AC: 9180 AN: 53414

Middle Eastern (MID) AF: 0.122 AC: 700 AN: 5740

European-Non Finnish (NFE) AF: 0.110 AC: 121888 AN: 1104058

Other (OTH) AF: 0.113 AC: 6797 AN: 60104

GnomAD4 genome AF: 0.116 AC: 17666 AN: 152016 Hom.: 1089 Cov.: 31 AF XY: 0.118 AC XY: 8764 AN XY: 74296

African (AFR) AF: 0.114 AC: 4738 AN: 41454

American (AMR) AF: 0.0757 AC: 1157 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 384 AN: 3464

East Asian (EAS) AF: 0.0905 AC: 467 AN: 5160

South Asian (SAS) AF: 0.152 AC: 730 AN: 4810

European-Finnish (FIN) AF: 0.175 AC: 1847 AN: 10562

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.118 AC: 7997 AN: 67970

Other (OTH) AF: 0.130 AC: 273 AN: 2108

Alfa AF: 0.116 Hom.: 1757

Bravo AF: 0.106

Asia WGS AF: 0.169 AC: 587 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.9
DANN	Benign	0.81
PhyloP100		-0.025
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

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: rs2547547; hg19: chr5-141005687; COSMIC: COSV59497907; COSMIC: COSV59497907;