NM_001378414.1:c.743C>T

Variant names:

• chr2-239144705-G-A
• rs1064797002
• NM_001378414.1:c.743C>T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_001378414.1(HDAC4):​c.743C>T​(p.Pro248Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P248A) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: HDAC4 NM_001378414.1 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 9.01
• Publications: 2 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: Pathogenic. The variant received 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-239144706-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 1344563.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.863
• PP5: Variant 2-239144705-G-A is Pathogenic according to our data. Variant chr2-239144705-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 424498.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.743C>T	p.Pro248Leu	missense	Exon 8 of 27	NP_001365343.1	A0A7I2SVS4
	HDAC4	NM_001378415.1		c.743C>T	p.Pro248Leu	missense	Exon 8 of 27	NP_001365344.1	A0A7I2SVS4
	HDAC4	NM_001378416.1		c.743C>T	p.Pro248Leu	missense	Exon 8 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.743C>T	p.Pro248Leu	missense	Exon 8 of 27	ENSP00000440481.3	A0A7I2SVS4
	HDAC4	ENST00000345617.7	TSL:1	c.743C>T	p.Pro248Leu	missense	Exon 8 of 27	ENSP00000264606.3	P56524-1
	HDAC4	ENST00000461113.5	TSL:1	n.406C>T		non_coding_transcript_exon	Exon 2 of 6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Neurodevelopmental disorder with central hypotonia and dysmorphic facies (3)
1	-	-	Chromosome 2q37 deletion syndrome (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	not provided (1)
1	-	-	Profound intellectual disability (1)
-	-	-	Brachydactyly syndrome type E (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.057	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Benign	-0.43	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		9.0
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-8.9	D
REVEL	Uncertain	0.47
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.33		Loss of glycosylation at P248 (P = 0.0323)
MVP		0.87
MPC		1.0
ClinPred		1.0	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.75
gMVP		0.51
Mutation Taster		=27/73	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1064797002; hg19: chr2-240066401; COSMIC: COSV61866558; COSMIC: COSV61866558;