17-28912612-C-T

Variant names:

• chr17-28912612-C-T
• rs144144007
• NM_001033561.2:c.1959G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Moderate BP6_Moderate BP7 BS1 BS2

The NM_001033561.2(PHF12):​c.1959G>A​(p.Pro653Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00318 in 1,614,164 control chromosomes in the GnomAD database, including 69 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0026 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (66 hom.)
• Consequence: PHF12 NM_001033561.2 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.13
• Publications: 1 publications found

Genes affected

PHF12 (HGNC:20816): (PHD finger protein 12) Enables phosphatidylinositol binding activity and transcription corepressor activity. Involved in negative regulation of transcription, DNA-templated. Acts upstream of or within negative regulation of transcription by RNA polymerase II. Located in nucleoplasm. Part of Sin3 complex and transcription repressor complex. [provided by Alliance of Genome Resources, Apr 2022]

PHF12 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• neurodevelopmental disorder

  Inheritance: AD Classification: STRONG Submitted by: G2P

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 17-28912612-C-T is Benign according to our data. Variant chr17-28912612-C-T is described in ClinVar as Benign. ClinVar VariationId is 790330.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.13 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00259 (394/152270) while in subpopulation SAS AF = 0.0224 (108/4824). AF 95% confidence interval is 0.019. There are 3 homozygotes in GnomAd4. There are 222 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 394 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001033561.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHF12	NM_001033561.2	MANE Select	c.1959G>A	p.Pro653Pro	synonymous	Exon 9 of 15	NP_001028733.1	Q96QT6-1
	PHF12	NM_001290131.2		c.1959G>A	p.Pro653Pro	synonymous	Exon 9 of 11	NP_001277060.1	Q96QT6-5
	PHF12	NM_020889.3		c.1959G>A	p.Pro653Pro	synonymous	Exon 9 of 9	NP_065940.1	Q96QT6-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHF12	ENST00000332830.9	TSL:2 MANE Select	c.1959G>A	p.Pro653Pro	synonymous	Exon 9 of 15	ENSP00000329933.4	Q96QT6-1
	PHF12	ENST00000577226.5	TSL:1	c.1959G>A	p.Pro653Pro	synonymous	Exon 9 of 11	ENSP00000465161.1	Q96QT6-5
	PHF12	ENST00000268756.7	TSL:1	c.1959G>A	p.Pro653Pro	synonymous	Exon 9 of 9	ENSP00000268756.3	Q96QT6-2

Frequencies

GnomAD3 genomes AF: 0.00259 AC: 394 AN: 152152 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000652

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00663

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0224

Gnomad FIN AF: 0.00425

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00219

Gnomad OTH AF: 0.00716

GnomAD2 exomes AF: 0.00510 AC: 1283 AN: 251474 AF XY: 0.00615

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.000781

Gnomad ASJ exome AF: 0.00774

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00388

Gnomad NFE exome AF: 0.00275

Gnomad OTH exome AF: 0.00472

GnomAD4 exome AF: 0.00324 AC: 4740 AN: 1461894 Hom.: 66 Cov.: 32 AF XY: 0.00389 AC XY: 2826 AN XY: 727248

African (AFR) AF: 0.000508 AC: 17 AN: 33480

American (AMR) AF: 0.000984 AC: 44 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00899 AC: 235 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0239 AC: 2062 AN: 86258

European-Finnish (FIN) AF: 0.00432 AC: 231 AN: 53420

Middle Eastern (MID) AF: 0.00659 AC: 38 AN: 5768

European-Non Finnish (NFE) AF: 0.00172 AC: 1917 AN: 1112012

Other (OTH) AF: 0.00321 AC: 194 AN: 60396

GnomAD4 genome AF: 0.00259 AC: 394 AN: 152270 Hom.: 3 Cov.: 32 AF XY: 0.00298 AC XY: 222 AN XY: 74446

African (AFR) AF: 0.000650 AC: 27 AN: 41536

American (AMR) AF: 0.00163 AC: 25 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00663 AC: 23 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5180

South Asian (SAS) AF: 0.0224 AC: 108 AN: 4824

European-Finnish (FIN) AF: 0.00425 AC: 45 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00219 AC: 149 AN: 68030

Other (OTH) AF: 0.00709 AC: 15 AN: 2116

Alfa AF: 0.00258 Hom.: 0

Bravo AF: 0.00180

Asia WGS AF: 0.00779 AC: 27 AN: 3478

EpiCase AF: 0.00273

EpiControl AF: 0.00172

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	10
DANN	Benign	0.85
PhyloP100		1.1
PromoterAI		0.0013	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	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

Other links and lift over

dbSNP: rs144144007; hg19: chr17-27239630; COSMIC: COSV52019951; COSMIC: COSV52019951;