11-45935741-TAAAAAAAAAAAAAA-TAAAAAAAAAAAAAAA

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_001352027.3(PHF21A):​c.1685-3dupT 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.012 (20 hom., cov: 0)
  • Exomes 𝑓: 0.0094 (0 hom.)
• Consequence: PHF21A NM_001352027.3 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• 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 -8 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0118 (1274/108314) while in subpopulation AFR AF = 0.0392 (1122/28604). AF 95% confidence interval is 0.0373. There are 20 homozygotes in GnomAd4. There are 594 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1274 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHF21A	NM_001352027.3	c.1685-3dupT		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.1685-3_1685-2insT		splice_region_variant, intron_variant	Intron 17 of 18		NM_001352027.3	ENSP00000502222.1

Frequencies

GnomAD3 genomes AF: 0.0118 AC: 1274 AN: 108302 Hom.: 20 Cov.: 0

Gnomad AFR AF: 0.0393

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00398

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00618

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00424

Gnomad NFE AF: 0.00141

Gnomad OTH AF: 0.0104

GnomAD2 exomes AF: 0.0132 AC: 637 AN: 48272 AF XY: 0.0126

Gnomad AFR exome AF: 0.0282

Gnomad AMR exome AF: 0.0128

Gnomad ASJ exome AF: 0.0101

Gnomad EAS exome AF: 0.0139

Gnomad FIN exome AF: 0.00244

Gnomad NFE exome AF: 0.0106

Gnomad OTH exome AF: 0.0167

GnomAD4 exome AF: 0.00944 AC: 3896 AN: 412924 Hom.: 0 Cov.: 0 AF XY: 0.00950 AC XY: 2072 AN XY: 218126

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

African (AFR) AF: 0.0281 AC: 296 AN: 10524

American (AMR) AF: 0.00892 AC: 150 AN: 16814

Ashkenazi Jewish (ASJ) AF: 0.00795 AC: 95 AN: 11952

East Asian (EAS) AF: 0.00699 AC: 180 AN: 25744

South Asian (SAS) AF: 0.0160 AC: 628 AN: 39290

European-Finnish (FIN) AF: 0.00537 AC: 140 AN: 26080

Middle Eastern (MID) AF: 0.00547 AC: 12 AN: 2192

European-Non Finnish (NFE) AF: 0.00843 AC: 2181 AN: 258848

Other (OTH) AF: 0.00996 AC: 214 AN: 21480

⚠️ 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: 0.0118 AC: 1274 AN: 108314 Hom.: 20 Cov.: 0 AF XY: 0.0118 AC XY: 594 AN XY: 50164

African (AFR) AF: 0.0392 AC: 1122 AN: 28604

American (AMR) AF: 0.00397 AC: 41 AN: 10322

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

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

South Asian (SAS) AF: 0.00623 AC: 19 AN: 3052

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3552

Middle Eastern (MID) AF: 0.00463 AC: 1 AN: 216

European-Non Finnish (NFE) AF: 0.00141 AC: 76 AN: 53764

Other (OTH) AF: 0.0104 AC: 15 AN: 1440

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.0
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: rs35995547; hg19: chr11-45957292;