rs190059174

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr2-239052959-G-A
• chr2-239052959-G-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.*138C>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 0.00947 in 999,266 control chromosomes in the GnomAD database, including 72 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0082 (16 hom., cov: 33)
  • Exomes 𝑓: 0.0097 (56 hom.)
• Consequence: HDAC4 NM_001378414.1 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.257
• Publications: 1 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=-0.79).
• BP6: Variant 2-239052959-G-A is Benign according to our data. Variant chr2-239052959-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1214616.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00823 (1254/152362) while in subpopulation NFE AF = 0.0127 (867/68038). AF 95% confidence interval is 0.012. There are 16 homozygotes in GnomAd4. There are 614 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1254 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.*138C>T		3_prime_UTR	Exon 27 of 27	NP_001365343.1	A0A7I2SVS4
	HDAC4	NM_001378415.1		c.*138C>T		3_prime_UTR	Exon 27 of 27	NP_001365344.1	A0A7I2SVS4
	HDAC4	NM_001378416.1		c.*138C>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.*138C>T		3_prime_UTR	Exon 27 of 27	ENSP00000440481.3	A0A7I2SVS4
	HDAC4	ENST00000345617.7	TSL:1	c.*138C>T		3_prime_UTR	Exon 27 of 27	ENSP00000264606.3	P56524-1
	HDAC4	ENST00000896768.1		c.*138C>T		3_prime_UTR	Exon 27 of 27	ENSP00000566827.1

Frequencies

GnomAD3 genomes AF: 0.00824 AC: 1254 AN: 152244 Hom.: 16 Cov.: 33

Gnomad AFR AF: 0.00137

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.0167

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.0209

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0127

Gnomad OTH AF: 0.00478

GnomAD4 exome AF: 0.00970 AC: 8211 AN: 846904 Hom.: 56 Cov.: 12 AF XY: 0.00939 AC XY: 4175 AN XY: 444480

African (AFR) AF: 0.00121 AC: 26 AN: 21464

American (AMR) AF: 0.00217 AC: 91 AN: 41850

Ashkenazi Jewish (ASJ) AF: 0.0173 AC: 373 AN: 21620

East Asian (EAS) AF: 0.0000550 AC: 2 AN: 36348

South Asian (SAS) AF: 0.00226 AC: 164 AN: 72700

European-Finnish (FIN) AF: 0.0214 AC: 1066 AN: 49864

Middle Eastern (MID) AF: 0.000661 AC: 3 AN: 4542

European-Non Finnish (NFE) AF: 0.0110 AC: 6131 AN: 558442

Other (OTH) AF: 0.00886 AC: 355 AN: 40074

GnomAD4 genome AF: 0.00823 AC: 1254 AN: 152362 Hom.: 16 Cov.: 33 AF XY: 0.00824 AC XY: 614 AN XY: 74492

African (AFR) AF: 0.00137 AC: 57 AN: 41590

American (AMR) AF: 0.00189 AC: 29 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.0167 AC: 58 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4828

European-Finnish (FIN) AF: 0.0209 AC: 222 AN: 10628

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

European-Non Finnish (NFE) AF: 0.0127 AC: 867 AN: 68038

Other (OTH) AF: 0.00473 AC: 10 AN: 2116

Alfa AF: 0.0148 Hom.: 6

Bravo AF: 0.00587

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: 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	-0.79
CADD	Benign	7.1
DANN	Benign	0.90
PhyloP100		-0.26
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: rs190059174; hg19: chr2-239974655;