11-45935741-TAAAAAAAAAAAAAA-TAAAAAAAAAA

Variant names:

• chr11-45935741-TAAAA-T
• rs35995547
• NM_001352027.3:c.1685-6_1685-3delTTTT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001352027.3(PHF21A):​c.1685-6_1685-3delTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0388 in 510,102 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. 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 0.000046 (0 hom., cov: 0)
  • Exomes 𝑓: 0.049 (0 hom.)
• Consequence: PHF21A NM_001352027.3 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHF21A	NM_001352027.3	c.1685-6_1685-3delTTTT		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.1685-6_1685-3delTTTT		splice_region_variant, intron_variant	Intron 17 of 18		NM_001352027.3	ENSP00000502222.1

Frequencies

GnomAD3 genomes AF: 0.0000462 AC: 5 AN: 108326 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000350

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000844

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000186

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0423 AC: 2043 AN: 48272 AF XY: 0.0442

Gnomad AFR exome AF: 0.0340

Gnomad AMR exome AF: 0.0656

Gnomad ASJ exome AF: 0.0329

Gnomad EAS exome AF: 0.0515

Gnomad FIN exome AF: 0.0274

Gnomad NFE exome AF: 0.0368

Gnomad OTH exome AF: 0.0480

GnomAD4 exome AF: 0.0493 AC: 19807 AN: 401764 Hom.: 0 AF XY: 0.0489 AC XY: 10376 AN XY: 212292

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

African (AFR) AF: 0.0455 AC: 470 AN: 10332

American (AMR) AF: 0.0557 AC: 907 AN: 16298

Ashkenazi Jewish (ASJ) AF: 0.0472 AC: 548 AN: 11614

East Asian (EAS) AF: 0.0515 AC: 1276 AN: 24796

South Asian (SAS) AF: 0.0459 AC: 1768 AN: 38544

European-Finnish (FIN) AF: 0.0472 AC: 1195 AN: 25294

Middle Eastern (MID) AF: 0.0330 AC: 71 AN: 2152

European-Non Finnish (NFE) AF: 0.0494 AC: 12440 AN: 251830

Other (OTH) AF: 0.0542 AC: 1132 AN: 20904

⚠️ 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: 0.0000462 AC: 5 AN: 108338 Hom.: 0 Cov.: 0 AF XY: 0.0000797 AC XY: 4 AN XY: 50170

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

African (AFR) AF: 0.0000349 AC: 1 AN: 28620

American (AMR) AF: 0.00 AC: 0 AN: 10324

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: 0.000844 AC: 3 AN: 3554

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

European-Non Finnish (NFE) AF: 0.0000186 AC: 1 AN: 53768

Other (OTH) AF: 0.00 AC: 0 AN: 1440

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0151062), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

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;