6-63684419-G-A

Variant names:

• chr6-63684419-G-A
• rs114037821
• NM_001370348.2:c.697G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001370348.2(PHF3):​c.697G>A​(p.Gly233Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00133 in 1,613,986 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0066 (11 hom., cov: 32)
  • Exomes 𝑓: 0.00078 (16 hom.)
• Consequence: PHF3 NM_001370348.2 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 3.88

Genes affected

PHF3 (HGNC:8921): (PHD finger protein 3) This gene encodes a member of a PHD finger-containing gene family. This gene may function as a transcription factor and may be involved in glioblastomas development. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2014]

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023934245).
• BP6: Variant 6-63684419-G-A is Benign according to our data. Variant chr6-63684419-G-A is described in ClinVar as [Benign]. Clinvar id is 3041920.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0066 (1005/152260) while in subpopulation AFR AF = 0.0223 (926/41548). AF 95% confidence interval is 0.0211. There are 11 homozygotes in GnomAd4. There are 463 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHF3	NM_001370348.2	c.697G>A	p.Gly233Arg	missense_variant	Exon 4 of 16	ENST00000262043.8	NP_001357277.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHF3	ENST00000262043.8	c.697G>A	p.Gly233Arg	missense_variant	Exon 4 of 16	5	NM_001370348.2	ENSP00000262043.4

Frequencies

GnomAD3 genomes AF: 0.00659 AC: 1003 AN: 152142 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.0223

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00380

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00185 AC: 465 AN: 251262 AF XY: 0.00147

Gnomad AFR exome AF: 0.0229

Gnomad AMR exome AF: 0.00174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000176

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.000781 AC: 1142 AN: 1461726 Hom.: 16 Cov.: 32 AF XY: 0.000710 AC XY: 516 AN XY: 727166

Gnomad4 AFR exome AF: 0.0249 AC: 835 AN: 33470

Gnomad4 AMR exome AF: 0.00197 AC: 88 AN: 44724

Gnomad4 ASJ exome AF: 0.0000383 AC: 1 AN: 26132

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39686

Gnomad4 SAS exome AF: 0.0000580 AC: 5 AN: 86256

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53406

Gnomad4 NFE exome AF: 0.0000872 AC: 97 AN: 1111894

Gnomad4 Remaining exome AF: 0.00171 AC: 103 AN: 60390

GnomAD4 genome AF: 0.00660 AC: 1005 AN: 152260 Hom.: 11 Cov.: 32 AF XY: 0.00622 AC XY: 463 AN XY: 74436

Gnomad4 AFR AF: 0.0223 AC: 0.0222875 AN: 0.0222875

Gnomad4 AMR AF: 0.00379 AC: 0.00379234 AN: 0.00379234

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.000207 AC: 0.000207211 AN: 0.000207211

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000162 AC: 0.00016175 AN: 0.00016175

Gnomad4 OTH AF: 0.00378 AC: 0.0037843 AN: 0.0037843

Alfa AF: 0.00256 Hom.: 12

Bravo AF: 0.00744

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0232 AC: 102

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00203 AC: 246

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

PHF3-related disorder Benign:1

Jun 15, 2021

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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	0.11
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	19
DANN	Benign	0.89
DEOGEN2	Benign	0.019	.;T;T;T;.;T
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.075
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.84	T;T;T;.;T;T
MetaRNN	Benign	0.0024	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	.;.;.;L;.;L
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.34	N;N;N;N;N;N
REVEL	Benign	0.080
Sift	Benign	0.097	T;T;T;T;T;T
Sift4G	Benign	0.50	T;T;T;T;T;T
Polyphen		0.22, 0.62	.;.;.;B;P;B
Vest4		0.30, 0.15, 0.34
MutPred		0.097		.;.;.;Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);
MVP		0.068
MPC		0.10
ClinPred		0.014	T
GERP RS		4.8
Varity_R		0.089
gMVP		0.12
Mutation Taster		=95/5	polymorphism

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: rs114037821; hg19: chr6-64394320; COSMIC: COSV99029795; COSMIC: COSV99029795;