Genetic Variant NM_001352027.3:c.1685-4_1685-3dupTT (chr11-45935741-T-TAA) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6BS2

The NM_001352027.3(PHF21A):c.1685-4_1685-3dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.0027 ( 1 hom., cov: 0)

Exomes 𝑓: 0.0015 ( 0 hom. )

Consequence

PHF21A
NM_001352027.3 splice_region, intron

Scores

Not classified

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: 0.00

Publications

2 publications found

Variant links:

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

PHF21A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP6

Variant 11-45935741-T-TAA is Benign according to our data. Variant chr11-45935741-T-TAA is described in ClinVar as Likely_benign. ClinVar VariationId is 3042619.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High AC in GnomAd4 at 292 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHF21A	NM_001352027.3 link	c.1685-4_1685-3dupTT		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 link	c.1685-3_1685-2insTT		splice_region_variant, intron_variant	Intron 17 of 18		NM_001352027.3	ENSP00000502222.1		Q96BD5-3

Frequencies

GnomAD3 genomes

AF:

0.00270

AC:

293

AN:

108322

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00974

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00116

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00139

GnomAD4 exome

AF:

0.00150

AC:

621

AN:

414452

Hom.:

Cov.:

AF XY:

0.00156

AC XY:

341

AN XY:

218948

show subpopulations

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

African (AFR)

AF:

0.00738

AC:

AN:

10576

American (AMR)

AF:

0.00142

AC:

AN:

16866

Ashkenazi Jewish (ASJ)

AF:

0.000918

AC:

AN:

11988

East Asian (EAS)

AF:

0.00155

AC:

AN:

25838

South Asian (SAS)

AF:

0.00284

AC:

112

AN:

39486

European-Finnish (FIN)

AF:

0.000688

AC:

AN:

26178

Middle Eastern (MID)

AF:

0.000454

AC:

AN:

2204

European-Non Finnish (NFE)

AF:

0.00114

AC:

295

AN:

259752

Other (OTH)

AF:

0.00195

AC:

AN:

21564

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.276

Heterozygous variant carriers

117

175

234

292

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00270

AC:

292

AN:

108332

Hom.:

Cov.:

AF XY:

0.00281

AC XY:

141

AN XY:

50174

show subpopulations

African (AFR)

AF:

0.00972

AC:

278

AN:

28610

American (AMR)

AF:

0.00107

AC:

AN:

10328

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2910

East Asian (EAS)

AF:

0.00

AC:

AN:

3722

South Asian (SAS)

AF:

0.00

AC:

AN:

3052

European-Finnish (FIN)

AF:

0.000282

AC:

AN:

3552

Middle Eastern (MID)

AF:

0.00

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53770

Other (OTH)

AF:

0.00139

AC:

AN:

1440

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

PHF21A-related disorder

Benign:1

Oct 01, 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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.0

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over