11-45935741-TAAAAAAAAAAAAAA-TAAAAAAAAAAAAA

Variant names:

• chr11-45935741-TA-T
• rs35995547
• NM_001352027.3:c.1685-3delT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_001352027.3(PHF21A):​c.1685-3delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.80 (34711 hom., cov: 0)
  • Exomes 𝑓: 0.30 (400 hom.)
• Consequence: PHF21A NM_001352027.3 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter 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: Benign. The variant received -10 ACMG points.

• BP6: Variant 11-45935741-TA-T is Benign according to our data. Variant chr11-45935741-TA-T is described in ClinVar as Benign. ClinVar VariationId is 403296.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.871 is higher than 0.05.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.798 AC: 86505 AN: 108348 Hom.: 34720 Cov.: 0

Gnomad AFR AF: 0.625

Gnomad AMI AF: 0.758

Gnomad AMR AF: 0.875

Gnomad ASJ AF: 0.849

Gnomad EAS AF: 0.897

Gnomad SAS AF: 0.764

Gnomad FIN AF: 0.896

Gnomad MID AF: 0.826

Gnomad NFE AF: 0.862

Gnomad OTH AF: 0.803

GnomAD2 exomes AF: 0.136 AC: 6579 AN: 48272 AF XY: 0.133

Gnomad AFR exome AF: 0.129

Gnomad AMR exome AF: 0.211

Gnomad ASJ exome AF: 0.114

Gnomad EAS exome AF: 0.187

Gnomad FIN exome AF: 0.0451

Gnomad NFE exome AF: 0.113

Gnomad OTH exome AF: 0.166

GnomAD4 exome AF: 0.300 AC: 122818 AN: 409354 Hom.: 400 Cov.: 0 AF XY: 0.292 AC XY: 63250 AN XY: 216270

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

African (AFR) AF: 0.259 AC: 2721 AN: 10498

American (AMR) AF: 0.254 AC: 4210 AN: 16590

Ashkenazi Jewish (ASJ) AF: 0.277 AC: 3284 AN: 11842

East Asian (EAS) AF: 0.320 AC: 8162 AN: 25538

South Asian (SAS) AF: 0.206 AC: 8057 AN: 39052

European-Finnish (FIN) AF: 0.302 AC: 7797 AN: 25776

Middle Eastern (MID) AF: 0.235 AC: 514 AN: 2184

European-Non Finnish (NFE) AF: 0.318 AC: 81532 AN: 256562

Other (OTH) AF: 0.307 AC: 6541 AN: 21312

⚠️ 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: 0.798 AC: 86497 AN: 108360 Hom.: 34711 Cov.: 0 AF XY: 0.796 AC XY: 39974 AN XY: 50196

African (AFR) AF: 0.624 AC: 17870 AN: 28620

American (AMR) AF: 0.876 AC: 9045 AN: 10330

Ashkenazi Jewish (ASJ) AF: 0.849 AC: 2471 AN: 2910

East Asian (EAS) AF: 0.897 AC: 3338 AN: 3722

South Asian (SAS) AF: 0.764 AC: 2329 AN: 3050

European-Finnish (FIN) AF: 0.896 AC: 3189 AN: 3560

Middle Eastern (MID) AF: 0.810 AC: 175 AN: 216

European-Non Finnish (NFE) AF: 0.862 AC: 46367 AN: 53780

Other (OTH) AF: 0.804 AC: 1158 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		0.0
Mutation Taster		=99/1	polymorphism (auto)

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: rs35995547; hg19: chr11-45957292; COSMIC: COSV57655087; COSMIC: COSV57655087;