11-45933999-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS2

The NM_001352027.3(PHF21A):c.2015C>T(p.Ala672Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000929 in 1,593,080 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A672A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00049 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000051 (0 hom.)
• Consequence: PHF21A NM_001352027.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.302

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]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• PP2: Missense variant where missense usually causes diseases, PHF21A
• BP4: Computational evidence support a benign effect (MetaRNN=0.014741302).
• BP6: Variant 11-45933999-G-A is Benign according to our data. Variant chr11-45933999-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1595935.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 75 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHF21A	NM_001352027.3	c.2015C>T	p.Ala672Val	missense_variant	19/19	ENST00000676320.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHF21A	ENST00000676320.1	c.2015C>T	p.Ala672Val	missense_variant	19/19		NM_001352027.3	P3

Frequencies

GnomAD3 genomes AF: 0.000493 AC: 75 AN: 152162 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00167

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

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

GnomAD3 exomes AF: 0.000120 AC: 28 AN: 233658 Hom.: 0 AF XY: 0.000119 AC XY: 15 AN XY: 126564

Gnomad AFR exome AF: 0.00157

Gnomad AMR exome AF: 0.0000328

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000935

Gnomad OTH exome AF: 0.000179

GnomAD4 exome AF: 0.0000507 AC: 73 AN: 1440800 Hom.: 0 Cov.: 31 AF XY: 0.0000461 AC XY: 33 AN XY: 715996

Gnomad4 AFR exome AF: 0.00160

Gnomad4 AMR exome AF: 0.000124

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000102

Gnomad4 SAS exome AF: 0.0000239

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000168

GnomAD4 genome AF: 0.000493 AC: 75 AN: 152280 Hom.: 0 Cov.: 32 AF XY: 0.000510 AC XY: 38 AN XY: 74462

Gnomad4 AFR AF: 0.00166

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000784 Hom.: 0

Bravo AF: 0.000620

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000173 AC: 21

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	PHF21A: BP4, BS1 -

PHF21A-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 18, 2022

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
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	-0.020
Cadd	Benign	12
Dann	Benign	0.89
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.77	T;T;T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.015	T;T;T
MetaSVM	Benign	-0.49	T
MutationTaster	Benign	0.89	N;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.53	N;N;N
REVEL	Uncertain	0.48
Sift	Benign	0.23	T;T;T
Sift4G	Benign	0.77	T;T;.
Polyphen		0.0010	B;B;.
Vest4		0.071
MVP		0.98
MPC		0.11
ClinPred		0.0090	T
GERP RS		-2.6
Varity_R		0.046
gMVP		0.47

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

Publications

LitVar

Other links and lift over

dbSNP: rs149898933; hg19: chr11-45955550; COSMIC: COSV57658840; COSMIC: COSV57658840;