11-45934034-C-T

Variant names:

• chr11-45934034-C-T
• rs144966693
• NM_001352027.3:c.1980G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_001352027.3(PHF21A):​c.1980G>A​(p.Thr660Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000562 in 1,612,408 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00059 (2 hom.)
• Consequence: PHF21A NM_001352027.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.293
• 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 11-45934034-C-T is Benign according to our data. Variant chr11-45934034-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 719351.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 49 AD gene.

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.1980G>A	p.Thr660Thr	synonymous	Exon 19 of 19	NP_001338956.1	Q96BD5-3
	PHF21A	NM_001441167.1		c.2001G>A	p.Thr667Thr	synonymous	Exon 18 of 18	NP_001428096.1
	PHF21A	NM_001441168.1		c.2001G>A	p.Thr667Thr	synonymous	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.1980G>A	p.Thr660Thr	synonymous	Exon 19 of 19	ENSP00000502222.1	Q96BD5-3
	PHF21A	ENST00000323180.10	TSL:1	c.1839G>A	p.Thr613Thr	synonymous	Exon 18 of 18	ENSP00000323152.6	Q96BD5-2
	PHF21A	ENST00000863274.1		c.1998G>A	p.Thr666Thr	synonymous	Exon 18 of 18	ENSP00000533333.1

Frequencies

GnomAD3 genomes AF: 0.000322 AC: 49 AN: 152038 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000434 AC: 108 AN: 248998 AF XY: 0.000557

Gnomad AFR exome AF: 0.0000618

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.000304

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000534

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000587 AC: 857 AN: 1460252 Hom.: 2 Cov.: 31 AF XY: 0.000604 AC XY: 439 AN XY: 726412

African (AFR) AF: 0.0000299 AC: 1 AN: 33432

American (AMR) AF: 0.0000898 AC: 4 AN: 44546

Ashkenazi Jewish (ASJ) AF: 0.000269 AC: 7 AN: 25978

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39674

South Asian (SAS) AF: 0.000895 AC: 77 AN: 86052

European-Finnish (FIN) AF: 0.0000750 AC: 4 AN: 53326

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.000663 AC: 737 AN: 1111170

Other (OTH) AF: 0.000398 AC: 24 AN: 60318

GnomAD4 genome AF: 0.000322 AC: 49 AN: 152156 Hom.: 0 Cov.: 32 AF XY: 0.000296 AC XY: 22 AN XY: 74384

African (AFR) AF: 0.000169 AC: 7 AN: 41508

American (AMR) AF: 0.0000654 AC: 1 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5172

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

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

European-Non Finnish (NFE) AF: 0.000500 AC: 34 AN: 68002

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000488 Hom.: 0

Bravo AF: 0.000348

EpiCase AF: 0.000600

EpiControl AF: 0.000772

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	PHF21A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	4.9
DANN	Benign	0.88
PhyloP100		-0.29
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs144966693; hg19: chr11-45955585; COSMIC: COSV57654533; COSMIC: COSV57654533;