rs190130626

Variant names:

• chr2-239084138-A-G
• rs190130626
• NM_001378414.1:c.2532+17T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001378414.1(HDAC4):​c.2532+17T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000652 in 1,601,600 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00032 (5 hom.)
• Consequence: HDAC4 NM_001378414.1 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.797
• 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), G2P, Ambry Genetics
• 2q37 microdeletion syndrome

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 2-239084138-A-G is Benign according to our data. Variant chr2-239084138-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 445577.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00379 (577/152300) while in subpopulation AFR AF = 0.0133 (552/41554). AF 95% confidence interval is 0.0124. There are 3 homozygotes in GnomAd4. There are 257 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 577 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.2532+17T>C		intron	N/A	NP_001365343.1	A0A7I2SVS4
	HDAC4	NM_001378415.1		c.2532+17T>C		intron	N/A	NP_001365344.1	A0A7I2SVS4
	HDAC4	NM_001378416.1		c.2517+17T>C		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.2532+17T>C		intron	N/A	ENSP00000440481.3	A0A7I2SVS4
	HDAC4	ENST00000345617.7	TSL:1	c.2517+17T>C		intron	N/A	ENSP00000264606.3	P56524-1
	HDAC4	ENST00000896768.1		c.2532+17T>C		intron	N/A	ENSP00000566827.1

Frequencies

GnomAD3 genomes AF: 0.00377 AC: 573 AN: 152182 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.0132

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

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: 0.00239

GnomAD2 exomes AF: 0.000962 AC: 235 AN: 244180 AF XY: 0.000734

Gnomad AFR exome AF: 0.0141

Gnomad AMR exome AF: 0.000440

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000333

GnomAD4 exome AF: 0.000322 AC: 467 AN: 1449300 Hom.: 5 Cov.: 29 AF XY: 0.000263 AC XY: 190 AN XY: 721350

African (AFR) AF: 0.0125 AC: 414 AN: 33118

American (AMR) AF: 0.000451 AC: 20 AN: 44388

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26012

East Asian (EAS) AF: 0.00 AC: 0 AN: 39450

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85360

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53080

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

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1102122

Other (OTH) AF: 0.000500 AC: 30 AN: 60020

GnomAD4 genome AF: 0.00379 AC: 577 AN: 152300 Hom.: 3 Cov.: 33 AF XY: 0.00345 AC XY: 257 AN XY: 74482

African (AFR) AF: 0.0133 AC: 552 AN: 41554

American (AMR) AF: 0.00124 AC: 19 AN: 15306

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

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68024

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00188 Hom.: 0

Bravo AF: 0.00427

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.3
DANN	Benign	0.25
PhyloP100		-0.80
RBP_binding_hub_radar		0.67
RBP_regulation_power_radar		1.8
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: rs190130626; hg19: chr2-240005834;