11-45935741-TAAAAA-T

Variant names:

• chr11-45935741-TAAAAA-T
• rs35995547
• NM_001352027.3:c.1685-7_1685-3delTTTTT

Variant summary

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

The NM_001352027.3(PHF21A):​c.1685-7_1685-3delTTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0137 in 515,874 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.000065 (0 hom., cov: 0)
  • Exomes 𝑓: 0.017 (0 hom.)
• Consequence: PHF21A NM_001352027.3 splice_region, intron
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.62
• 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-TAAAAA-T is Benign according to our data. Variant chr11-45935741-TAAAAA-T is described in ClinVar as Benign. ClinVar VariationId is 3041678.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHF21A	NM_001352027.3	c.1685-7_1685-3delTTTTT		splice_region_variant, intron_variant	Intron 17 of 18	ENST00000676320.1	NP_001338956.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHF21A	ENST00000676320.1	c.1685-7_1685-3delTTTTT		splice_region_variant, intron_variant	Intron 17 of 18		NM_001352027.3	ENSP00000502222.1

Frequencies

GnomAD3 genomes AF: 0.0000646 AC: 7 AN: 108336 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000350

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000388

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: 0.0000186

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0148 AC: 716 AN: 48272 AF XY: 0.0157

Gnomad AFR exome AF: 0.00924

Gnomad AMR exome AF: 0.0231

Gnomad ASJ exome AF: 0.0133

Gnomad EAS exome AF: 0.0185

Gnomad FIN exome AF: 0.00853

Gnomad NFE exome AF: 0.0132

Gnomad OTH exome AF: 0.0195

GnomAD4 exome AF: 0.0174 AC: 7082 AN: 407538 Hom.: 0 AF XY: 0.0177 AC XY: 3803 AN XY: 215236

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

African (AFR) AF: 0.0159 AC: 167 AN: 10482

American (AMR) AF: 0.0199 AC: 329 AN: 16564

Ashkenazi Jewish (ASJ) AF: 0.0179 AC: 211 AN: 11768

East Asian (EAS) AF: 0.0168 AC: 425 AN: 25250

South Asian (SAS) AF: 0.0163 AC: 637 AN: 39100

European-Finnish (FIN) AF: 0.0164 AC: 420 AN: 25636

Middle Eastern (MID) AF: 0.0133 AC: 29 AN: 2178

European-Non Finnish (NFE) AF: 0.0175 AC: 4481 AN: 255344

Other (OTH) AF: 0.0181 AC: 383 AN: 21216

⚠️ 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: 0.0000646 AC: 7 AN: 108336 Hom.: 0 Cov.: 0 AF XY: 0.0000598 AC XY: 3 AN XY: 50148

African (AFR) AF: 0.0000350 AC: 1 AN: 28564

American (AMR) AF: 0.000388 AC: 4 AN: 10320

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 3728

South Asian (SAS) AF: 0.00 AC: 0 AN: 3076

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 236

European-Non Finnish (NFE) AF: 0.0000186 AC: 1 AN: 53782

Other (OTH) AF: 0.00 AC: 0 AN: 1436

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

PHF21A-related disorder Benign:1

Jan 13, 2020

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.6
Mutation Taster		=85/15	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;