chr11-45933982-C-T

Variant names:

• chr11-45933982-C-T
• rs991807725
• NM_001352027.3:c.2032G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001352027.3(PHF21A):​c.2032G>A​(p.Glu678Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000212 in 1,416,696 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PHF21A NM_001352027.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.08
• Publications: 0 publications found

Genes affected

PHF21A (HGNC:24156): (PHD finger protein 21A) The PHF21A gene encodes BHC80, a component of a BRAF35 (MIM 605535)/histone deacetylase (HDAC; see MIM 601241) complex (BHC) that mediates repression of neuron-specific genes through the cis-regulatory element known as repressor element-1 (RE1) or neural restrictive silencer (NRS) (Hakimi et al., 2002 [PubMed 12032298]).[supplied by OMIM, Nov 2010]

PHF21A Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Potocki-Shaffer syndrome

  Inheritance: AD Classification: STRONG Submitted by: G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11501762).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001352027.3. 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
	PHF21A	NM_001352027.3	MANE Select	c.2032G>A	p.Glu678Lys	missense	Exon 19 of 19	NP_001338956.1	Q96BD5-3
	PHF21A	NM_001441167.1		c.2053G>A	p.Glu685Lys	missense	Exon 18 of 18	NP_001428096.1
	PHF21A	NM_001441168.1		c.2053G>A	p.Glu685Lys	missense	Exon 19 of 19	NP_001428097.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHF21A	ENST00000676320.1	MANE Select	c.2032G>A	p.Glu678Lys	missense	Exon 19 of 19	ENSP00000502222.1	Q96BD5-3
	PHF21A	ENST00000323180.10	TSL:1	c.1891G>A	p.Glu631Lys	missense	Exon 18 of 18	ENSP00000323152.6	Q96BD5-2
	PHF21A	ENST00000863274.1		c.2050G>A	p.Glu684Lys	missense	Exon 18 of 18	ENSP00000533333.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 214876 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00

GnomAD4 exome AF: 0.00000212 AC: 3 AN: 1416696 Hom.: 0 Cov.: 31 AF XY: 0.00000428 AC XY: 3 AN XY: 701390

African (AFR) AF: 0.00 AC: 0 AN: 31640

American (AMR) AF: 0.0000273 AC: 1 AN: 36592

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23096

East Asian (EAS) AF: 0.00 AC: 0 AN: 39004

South Asian (SAS) AF: 0.00 AC: 0 AN: 79362

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51912

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5534

European-Non Finnish (NFE) AF: 0.00000183 AC: 2 AN: 1091262

Other (OTH) AF: 0.00 AC: 0 AN: 58294

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000604 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.077	T
Eigen	Benign	-0.0088
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.12	T
MetaSVM	Uncertain	0.39	D
MutationAssessor	Benign	0.34	N
PhyloP100		2.1
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.98	N
REVEL	Uncertain	0.43
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.085	T
Polyphen		0.058	B
Vest4		0.19
MutPred		0.13		Gain of ubiquitination at E677 (P = 0.0018)
MVP		0.69
MPC		0.14
ClinPred		0.48	T
GERP RS		5.6
Varity_R		0.21
gMVP		0.57
Mutation Taster		=90/10	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: rs991807725; hg19: chr11-45955533;