11-45935741-TAAAAAAAAAAAAAA-TAAAAAAAAAAAA

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_001352027.3(PHF21A):​c.1685-4_1685-3delTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.161 in 517,128 control chromosomes in the GnomAD database, including 44 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.017 (20 hom., cov: 0)
  • Exomes 𝑓: 0.20 (24 hom.)
• Consequence: PHF21A NM_001352027.3 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.117
• 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: Benign. The variant received -10 ACMG points.

• BP6: Variant 11-45935741-TAA-T is Benign according to our data. Variant chr11-45935741-TAA-T is described in ClinVar as Benign. ClinVar VariationId is 403295.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0173 (1876/108342) while in subpopulation AFR AF = 0.0315 (902/28618). AF 95% confidence interval is 0.0298. There are 20 homozygotes in GnomAd4. There are 875 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1876 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHF21A	NM_001352027.3	c.1685-4_1685-3delTT		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.1685-4_1685-3delTT		splice_region_variant, intron_variant	Intron 17 of 18		NM_001352027.3	ENSP00000502222.1

Frequencies

GnomAD3 genomes AF: 0.0173 AC: 1876 AN: 108330 Hom.: 20 Cov.: 0

Gnomad AFR AF: 0.0316

Gnomad AMI AF: 0.00273

Gnomad AMR AF: 0.00824

Gnomad ASJ AF: 0.0144

Gnomad EAS AF: 0.00617

Gnomad SAS AF: 0.0163

Gnomad FIN AF: 0.0118

Gnomad MID AF: 0.0169

Gnomad NFE AF: 0.0131

Gnomad OTH AF: 0.0132

GnomAD2 exomes AF: 0.115 AC: 5550 AN: 48272 AF XY: 0.109

Gnomad AFR exome AF: 0.0974

Gnomad AMR exome AF: 0.162

Gnomad ASJ exome AF: 0.0933

Gnomad EAS exome AF: 0.164

Gnomad FIN exome AF: 0.0487

Gnomad NFE exome AF: 0.103

Gnomad OTH exome AF: 0.130

GnomAD4 exome AF: 0.199 AC: 81154 AN: 408786 Hom.: 24 AF XY: 0.195 AC XY: 42138 AN XY: 215876

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

African (AFR) AF: 0.188 AC: 1956 AN: 10404

American (AMR) AF: 0.168 AC: 2804 AN: 16710

Ashkenazi Jewish (ASJ) AF: 0.184 AC: 2175 AN: 11828

East Asian (EAS) AF: 0.204 AC: 5196 AN: 25474

South Asian (SAS) AF: 0.158 AC: 6143 AN: 38828

European-Finnish (FIN) AF: 0.197 AC: 5079 AN: 25758

Middle Eastern (MID) AF: 0.157 AC: 342 AN: 2172

European-Non Finnish (NFE) AF: 0.207 AC: 53149 AN: 256384

Other (OTH) AF: 0.203 AC: 4310 AN: 21228

⚠️ 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: 0.0173 AC: 1876 AN: 108342 Hom.: 20 Cov.: 0 AF XY: 0.0174 AC XY: 875 AN XY: 50172

African (AFR) AF: 0.0315 AC: 902 AN: 28618

American (AMR) AF: 0.00833 AC: 86 AN: 10326

Ashkenazi Jewish (ASJ) AF: 0.0144 AC: 42 AN: 2910

East Asian (EAS) AF: 0.00618 AC: 23 AN: 3724

South Asian (SAS) AF: 0.0157 AC: 48 AN: 3052

European-Finnish (FIN) AF: 0.0118 AC: 42 AN: 3550

Middle Eastern (MID) AF: 0.0185 AC: 4 AN: 216

European-Non Finnish (NFE) AF: 0.0131 AC: 707 AN: 53774

Other (OTH) AF: 0.0139 AC: 20 AN: 1440

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.12
Mutation Taster		=98/2	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: rs35995547; hg19: chr11-45957292;