11-45934077-T-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001352027.3(PHF21A):c.1937A>G(p.Asn646Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00047 in 1,613,976 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0028 (16 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (7 hom.)
• Consequence: PHF21A NM_001352027.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.66

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 -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, PHF21A
• BP4: Computational evidence support a benign effect (MetaRNN=0.007928789).
• BP6: Variant 11-45934077-T-C is Benign according to our data. Variant chr11-45934077-T-C is described in ClinVar as [Benign]. Clinvar id is 1618357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00276 (420/152182) while in subpopulation AMR AF= 0.0268 (410/15278). AF 95% confidence interval is 0.0247. There are 16 homozygotes in gnomad4. There are 293 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 420 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHF21A	NM_001352027.3	c.1937A>G	p.Asn646Ser	missense_variant	19/19	ENST00000676320.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHF21A	ENST00000676320.1	c.1937A>G	p.Asn646Ser	missense_variant	19/19		NM_001352027.3	P3

Frequencies

GnomAD3 genomes AF: 0.00276 AC: 420 AN: 152064 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0269

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000894 AC: 224 AN: 250564 Hom.: 5 AF XY: 0.000922 AC XY: 125 AN XY: 135566

Gnomad AFR exome AF: 0.0000621

Gnomad AMR exome AF: 0.00614

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000442

Gnomad OTH exome AF: 0.000655

GnomAD4 exome AF: 0.000232 AC: 339 AN: 1461794 Hom.: 7 Cov.: 32 AF XY: 0.000245 AC XY: 178 AN XY: 727202

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.00635

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000225

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.00276 AC: 420 AN: 152182 Hom.: 16 Cov.: 32 AF XY: 0.00394 AC XY: 293 AN XY: 74412

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.0268

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000133 Hom.: 0

Bravo AF: 0.00260

ExAC AF: 0.0000906 AC: 11

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

PHF21A-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 01, 2021

This variant is classified as 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	0.072
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.19
Cadd	Benign	21
Dann	Uncertain	0.99
Eigen	Benign	0.12
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.0079	T;T;T
MetaSVM	Uncertain	0.17	D
MutationTaster	Benign	0.86	D;D;D
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.030	N;N;N
REVEL	Benign	0.25
Sift	Uncertain	0.013	D;D;T
Sift4G	Benign	0.56	T;T;.
Polyphen		0.74	P;P;.
Vest4		0.31
MVP		0.62
MPC		0.16
ClinPred		0.068	T
GERP RS		5.8
Varity_R		0.12
gMVP		0.34

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: rs191903911; hg19: chr11-45955628;