chr11-45935741-T-TAA

Variant names:

• chr11-45935741-T-TAA
• rs35995547
• NM_001352027.3:c.1685-4_1685-3dupTT

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6 BS2

The NM_001352027.3(PHF21A):​c.1685-4_1685-3dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0027 (1 hom., cov: 0)
  • Exomes 𝑓: 0.0015 (0 hom.)
• Consequence: PHF21A NM_001352027.3 splice_region, intron
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.00
• Publications: 2 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: Likely_benign. The variant received -5 ACMG points.

• BP6: Variant 11-45935741-T-TAA is Benign according to our data. Variant chr11-45935741-T-TAA is described in ClinVar as Likely_benign. ClinVar VariationId is 3042619.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High AC in GnomAd4 at 292 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHF21A	NM_001352027.3	MANE Select	c.1685-4_1685-3dupTT		splice_region intron	N/A	NP_001338956.1
	PHF21A	NM_001441167.1		c.1706-4_1706-3dupTT		splice_region intron	N/A	NP_001428096.1
	PHF21A	NM_001441168.1		c.1706-4_1706-3dupTT		splice_region intron	N/A	NP_001428097.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHF21A	ENST00000676320.1	MANE Select	c.1685-3_1685-2insTT		splice_region intron	N/A	ENSP00000502222.1
	PHF21A	ENST00000323180.10	TSL:1	c.1544-3_1544-2insTT		splice_region intron	N/A	ENSP00000323152.6
	PHF21A	ENST00000418153.6	TSL:2	c.1682-3_1682-2insTT		splice_region intron	N/A	ENSP00000398824.2

Frequencies

GnomAD3 genomes AF: 0.00270 AC: 293 AN: 108322 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.00974

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00116

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00139

GnomAD4 exome AF: 0.00150 AC: 621 AN: 414452 Hom.: 0 Cov.: 0 AF XY: 0.00156 AC XY: 341 AN XY: 218948

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00738 AC: 78 AN: 10576

American (AMR) AF: 0.00142 AC: 24 AN: 16866

Ashkenazi Jewish (ASJ) AF: 0.000918 AC: 11 AN: 11988

East Asian (EAS) AF: 0.00155 AC: 40 AN: 25838

South Asian (SAS) AF: 0.00284 AC: 112 AN: 39486

European-Finnish (FIN) AF: 0.000688 AC: 18 AN: 26178

Middle Eastern (MID) AF: 0.000454 AC: 1 AN: 2204

European-Non Finnish (NFE) AF: 0.00114 AC: 295 AN: 259752

Other (OTH) AF: 0.00195 AC: 42 AN: 21564

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00270 AC: 292 AN: 108332 Hom.: 1 Cov.: 0 AF XY: 0.00281 AC XY: 141 AN XY: 50174

African (AFR) AF: 0.00972 AC: 278 AN: 28610

American (AMR) AF: 0.00107 AC: 11 AN: 10328

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2910

East Asian (EAS) AF: 0.00 AC: 0 AN: 3722

South Asian (SAS) AF: 0.00 AC: 0 AN: 3052

European-Finnish (FIN) AF: 0.000282 AC: 1 AN: 3552

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53770

Other (OTH) AF: 0.00139 AC: 2 AN: 1440

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

PHF21A-related disorder Benign:1

Oct 01, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.0
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs35995547; hg19: chr11-45957292;