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

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001352027.3(PHF21A):c.1685-5_1685-3dupTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000074 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00026 ( 0 hom. )

Consequence

PHF21A
NM_001352027.3 splice_region, intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

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: Labcorp Genetics (formerly Invitae), Ambry Genetics
Potocki-Shaffer syndrome
Inheritance: AD Classification: STRONG Submitted by: G2P

PHF21A links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_001352027.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAd4 at 8 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001352027.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PHF21A	NM_001352027.3	MANE Select	c.1685-5_1685-3dupTTT	splice_region intron	N/A	NP_001338956.1	Q96BD5-3
PHF21A	NM_001441167.1		c.1706-5_1706-3dupTTT	splice_region intron	N/A	NP_001428096.1
PHF21A	NM_001441168.1		c.1706-5_1706-3dupTTT	splice_region intron	N/A	NP_001428097.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PHF21A	ENST00000676320.1	MANE Select	c.1685-3_1685-2insTTT	splice_region intron	N/A	ENSP00000502222.1	Q96BD5-3
PHF21A	ENST00000323180.10	TSL:1	c.1544-3_1544-2insTTT	splice_region intron	N/A	ENSP00000323152.6	Q96BD5-2
PHF21A	ENST00000863274.1		c.1703-3_1703-2insTTT	splice_region intron	N/A	ENSP00000533333.1

Frequencies

GnomAD3 genomes

AF:

0.0000738

AC:

AN:

108336

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000280

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000263

AC:

109

AN:

415112

Hom.:

Cov.:

AF XY:

0.000265

AC XY:

AN XY:

219276

show subpopulations

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

African (AFR)

AF:

0.00141

AC:

AN:

10626

American (AMR)

AF:

0.000118

AC:

AN:

16914

Ashkenazi Jewish (ASJ)

AF:

0.0000834

AC:

AN:

11996

East Asian (EAS)

AF:

0.000154

AC:

AN:

25890

South Asian (SAS)

AF:

0.000657

AC:

AN:

39598

European-Finnish (FIN)

AF:

0.000153

AC:

AN:

26206

Middle Eastern (MID)

AF:

0.000453

AC:

AN:

2206

European-Non Finnish (NFE)

AF:

0.000196

AC:

AN:

260078

Other (OTH)

AF:

0.000232

AC:

AN:

21598

⚠️ 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: 0.291

Heterozygous variant carriers

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:

0.0000738

AC:

AN:

108348

Hom.:

Cov.:

AF XY:

0.0000199

AC XY:

AN XY:

50178

show subpopulations

African (AFR)

AF:

0.000280

AC:

AN:

28622

American (AMR)

AF:

0.00

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:

0.00

AC:

AN:

3552

Middle Eastern (MID)

AF:

0.00

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53774

Other (OTH)

AF:

0.00

AC:

AN:

1440

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.556

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.0

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over