ENST00000543185:c.*138C>G

Variant names:

• chr2-239052959-G-C
• rs190059174
• NM_001378414.1:c.*138C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000543185.6(HDAC4):​c.*138C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000118 in 846,974 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000012 (0 hom.)
• Consequence: HDAC4 ENST00000543185.6 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.257
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000543185.6. 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.*138C>G		3_prime_UTR	Exon 27 of 27	NP_001365343.1	A0A7I2SVS4
	HDAC4	NM_001378415.1		c.*138C>G		3_prime_UTR	Exon 27 of 27	NP_001365344.1	A0A7I2SVS4
	HDAC4	NM_001378416.1		c.*138C>G		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.*138C>G		3_prime_UTR	Exon 27 of 27	ENSP00000440481.3	A0A7I2SVS4
	HDAC4	ENST00000345617.7	TSL:1	c.*138C>G		3_prime_UTR	Exon 27 of 27	ENSP00000264606.3	P56524-1
	HDAC4	ENST00000896768.1		c.*138C>G		3_prime_UTR	Exon 27 of 27	ENSP00000566827.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000118 AC: 1 AN: 846974 Hom.: 0 Cov.: 12 AF XY: 0.00 AC XY: 0 AN XY: 444518

African (AFR) AF: 0.00 AC: 0 AN: 21464

American (AMR) AF: 0.00 AC: 0 AN: 41850

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21624

East Asian (EAS) AF: 0.00 AC: 0 AN: 36348

South Asian (SAS) AF: 0.00 AC: 0 AN: 72700

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49866

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4542

European-Non Finnish (NFE) AF: 0.00000179 AC: 1 AN: 558506

Other (OTH) AF: 0.00 AC: 0 AN: 40074

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.7
DANN	Benign	0.76
PhyloP100		-0.26

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: rs190059174; hg19: chr2-239974655;