11-45935741-TAAAAAAAAAAAAAA-TAAAAAAAA

Variant names:

• chr11-45935741-TAAAAAA-T
• rs35995547
• NM_001352027.3:c.1685-8_1685-3delTTTTTT

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_001352027.3(PHF21A):​c.1685-8_1685-3delTTTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00359 in 520,682 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0000092 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0045 (0 hom.)
• Consequence: PHF21A NM_001352027.3 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:2
• 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 -2 ACMG points.

• BP6: Variant 11-45935741-TAAAAAA-T is Benign according to our data. Variant chr11-45935741-TAAAAAA-T is described in ClinVar as Benign. ClinVar VariationId is 787908.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHF21A	NM_001352027.3	c.1685-8_1685-3delTTTTTT		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.1685-8_1685-3delTTTTTT		splice_region_variant, intron_variant	Intron 17 of 18		NM_001352027.3	ENSP00000502222.1

Frequencies

GnomAD3 genomes AF: 0.00000923 AC: 1 AN: 108334 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000186

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00453 AC: 1870 AN: 412348 Hom.: 0 AF XY: 0.00465 AC XY: 1014 AN XY: 217882

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

African (AFR) AF: 0.00303 AC: 32 AN: 10570

American (AMR) AF: 0.00536 AC: 90 AN: 16806

Ashkenazi Jewish (ASJ) AF: 0.00386 AC: 46 AN: 11926

East Asian (EAS) AF: 0.00362 AC: 93 AN: 25706

South Asian (SAS) AF: 0.00378 AC: 149 AN: 39418

European-Finnish (FIN) AF: 0.00427 AC: 111 AN: 25992

Middle Eastern (MID) AF: 0.00228 AC: 5 AN: 2190

European-Non Finnish (NFE) AF: 0.00484 AC: 1250 AN: 258266

Other (OTH) AF: 0.00438 AC: 94 AN: 21474

⚠️ 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: 0.00000923 AC: 1 AN: 108334 Hom.: 0 Cov.: 0 AF XY: 0.0000199 AC XY: 1 AN XY: 50144

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

African (AFR) AF: 0.00 AC: 0 AN: 28564

American (AMR) AF: 0.00 AC: 0 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: 0.00 AC: 0 AN: 3550

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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

PHF21A-related disorder Benign:1

Aug 09, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

not provided Benign:1

Aug 03, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.6
Mutation Taster		=82/18	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;