NM_001378414.1:c.*76C>T

Variant names:

• chr2-239053021-G-A
• rs13390561
• NM_001378414.1:c.*76C>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.*76C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00233 in 1,561,228 control chromosomes in the GnomAD database, including 83 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.012 (45 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (38 hom.)
• Consequence: HDAC4 NM_001378414.1 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.41
• 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=-0.63).
• BP6: Variant 2-239053021-G-A is Benign according to our data. Variant chr2-239053021-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1209358.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0117 (1786/152368) while in subpopulation AFR AF = 0.0412 (1713/41582). AF 95% confidence interval is 0.0396. There are 45 homozygotes in GnomAd4. There are 855 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1786 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.*76C>T		3_prime_UTR	Exon 27 of 27	NP_001365343.1	A0A7I2SVS4
	HDAC4	NM_001378415.1		c.*76C>T		3_prime_UTR	Exon 27 of 27	NP_001365344.1	A0A7I2SVS4
	HDAC4	NM_001378416.1		c.*76C>T		3_prime_UTR	Exon 27 of 27	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.*76C>T		3_prime_UTR	Exon 27 of 27	ENSP00000440481.3	A0A7I2SVS4
	HDAC4	ENST00000345617.7	TSL:1	c.*76C>T		3_prime_UTR	Exon 27 of 27	ENSP00000264606.3	P56524-1
	HDAC4	ENST00000896768.1		c.*76C>T		3_prime_UTR	Exon 27 of 27	ENSP00000566827.1

Frequencies

GnomAD3 genomes AF: 0.0117 AC: 1781 AN: 152250 Hom.: 45 Cov.: 33

Gnomad AFR AF: 0.0412

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00621

GnomAD4 exome AF: 0.00132 AC: 1854 AN: 1408860 Hom.: 38 Cov.: 24 AF XY: 0.00114 AC XY: 805 AN XY: 704002

African (AFR) AF: 0.0464 AC: 1501 AN: 32370

American (AMR) AF: 0.00181 AC: 81 AN: 44656

Ashkenazi Jewish (ASJ) AF: 0.0000388 AC: 1 AN: 25796

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39454

South Asian (SAS) AF: 0.000164 AC: 14 AN: 85192

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53240

Middle Eastern (MID) AF: 0.00317 AC: 18 AN: 5672

European-Non Finnish (NFE) AF: 0.0000479 AC: 51 AN: 1063768

Other (OTH) AF: 0.00313 AC: 184 AN: 58712

GnomAD4 genome AF: 0.0117 AC: 1786 AN: 152368 Hom.: 45 Cov.: 33 AF XY: 0.0115 AC XY: 855 AN XY: 74512

African (AFR) AF: 0.0412 AC: 1713 AN: 41582

American (AMR) AF: 0.00287 AC: 44 AN: 15312

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

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

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68040

Other (OTH) AF: 0.00615 AC: 13 AN: 2114

Alfa AF: 0.00341 Hom.: 4

Bravo AF: 0.0133

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely 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	-0.63
CADD	Benign	11
DANN	Benign	0.88
PhyloP100		1.4
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: rs13390561; hg19: chr2-239974717; COSMIC: COSV61862706; COSMIC: COSV61862706;