5-141636782-C-A

Variant names:

• chr5-141636782-C-A
• rs1562375699
• NM_003883.4:c.9G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003883.4(HDAC3):​c.9G>T​(p.Lys3Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,611,776 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: HDAC3 NM_003883.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.20
• Publications: 0 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]

RELL2 (HGNC:26902): (RELT like 2) Predicted to enable collagen binding activity. Involved in positive regulation of p38MAPK cascade. Predicted to be located in extracellular matrix. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18311772).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HDAC3	NM_003883.4	MANE Select	c.9G>T	p.Lys3Asn	missense	Exon 1 of 15	NP_003874.2
	HDAC3	NM_001355039.2		c.9G>T	p.Lys3Asn	missense	Exon 1 of 14	NP_001341968.1
	HDAC3	NM_001355040.2		c.-252G>T		5_prime_UTR	Exon 1 of 13	NP_001341969.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HDAC3	ENST00000305264.8	TSL:1 MANE Select	c.9G>T	p.Lys3Asn	missense	Exon 1 of 15	ENSP00000302967.3	O15379-1
	HDAC3	ENST00000937593.1		c.9G>T	p.Lys3Asn	missense	Exon 1 of 15	ENSP00000607652.1
	HDAC3	ENST00000856306.1		c.9G>T	p.Lys3Asn	missense	Exon 1 of 15	ENSP00000526365.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152172 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000402 AC: 1 AN: 249056 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000888

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1459604 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 726100

African (AFR) AF: 0.00 AC: 0 AN: 33390

American (AMR) AF: 0.00 AC: 0 AN: 44540

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26010

East Asian (EAS) AF: 0.00 AC: 0 AN: 39580

South Asian (SAS) AF: 0.00 AC: 0 AN: 86000

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53352

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1110710

Other (OTH) AF: 0.00 AC: 0 AN: 60272

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152172 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74336

African (AFR) AF: 0.00 AC: 0 AN: 41460

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.050	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.37	T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.083
FATHMM_MKL	Benign	0.50	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	1.9	L
PhyloP100		1.2
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.21
Sift	Uncertain	0.022	D
Sift4G	Uncertain	0.015	D
Polyphen		0.0010	B
Vest4		0.14
MutPred		0.32		Loss of methylation at K3 (P = 0.0032)
MVP		0.68
MPC		1.4
ClinPred		0.97	D
GERP RS		3.3
PromoterAI		-0.0024	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.77
gMVP		0.84
Mutation Taster		=77/23	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: rs1562375699; hg19: chr5-141016349;