Genetic Variant NM_004426.3:c.1284_1289delGCAGCA (chr12-8932728-CGCAGCA-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM4BP6_ModerateBS2

The NM_004426.3(PHC1):c.1284_1289delGCAGCA(p.Gln429_Gln430del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0185 in 151,848 control chromosomes in the GnomAD database, including 4 homozygotes. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.019 ( 4 hom., cov: 27)

Exomes 𝑓: 0.0020 ( 1 hom. )

Failed GnomAD Quality Control

Consequence

PHC1
NM_004426.3 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 3.09

Publications

2 publications found

Variant links:

Genes affected

PHC1 (HGNC:3182): (polyhomeotic homolog 1) This gene is a homolog of the Drosophila polyhomeotic gene, which is a member of the Polycomb group of genes. The gene product is a component of a multimeric protein complex that contains EDR2 and the vertebrate Polycomb protein BMH1. The gene product, the EDR2 protein, and the Drosophila polyhomeotic protein share 2 highly conserved domains, named homology domains I and II. These domains are involved in protein-protein interactions and may mediate heterodimerization of the protein encoded by this gene and the EDR2 protein. [provided by RefSeq, Jul 2008]

PHC1 Gene-Disease associations (from GenCC):

autosomal recessive primary microcephaly
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
microcephaly 11, primary, autosomal recessive
Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P

PHC1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

PM4

Nonframeshift variant in NON repetitive region in NM_004426.3.

BP6

Variant 12-8932728-CGCAGCA-C is Benign according to our data. Variant chr12-8932728-CGCAGCA-C is described in ClinVar as Benign. ClinVar VariationId is 376844.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004426.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PHC1	NM_004426.3	MANE Select	c.1284_1289delGCAGCA	p.Gln429_Gln430del	disruptive_inframe_deletion	Exon 8 of 15	NP_004417.2
PHC1	NM_001413738.1		c.1284_1289delGCAGCA	p.Gln429_Gln430del	disruptive_inframe_deletion	Exon 8 of 15	NP_001400667.1
PHC1	NM_001413739.1		c.1278_1283delGCAGCA	p.Gln427_Gln428del	disruptive_inframe_deletion	Exon 8 of 15	NP_001400668.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PHC1	ENST00000544916.6	TSL:1 MANE Select	c.1284_1289delGCAGCA	p.Gln429_Gln430del	disruptive_inframe_deletion	Exon 8 of 15	ENSP00000437659.1
PHC1	ENST00000543824.5	TSL:1	c.1284_1289delGCAGCA	p.Gln429_Gln430del	disruptive_inframe_deletion	Exon 9 of 16	ENSP00000440674.1
PHC1	ENST00000433083.6	TSL:1	c.1149_1154delGCAGCA	p.Gln384_Gln385del	disruptive_inframe_deletion	Exon 7 of 14	ENSP00000399194.2

Frequencies

GnomAD3 genomes

AF:

0.0185

AC:

2812

AN:

151732

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0622

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0142

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:

0.000250

Gnomad OTH

AF:

0.0120

GnomAD2 exomes

AF:

0.00385

AC:

955

AN:

248330

AF XY:

0.00285

show subpopulations

Gnomad AFR exome

AF:

0.0498

Gnomad AMR exome

AF:

0.00454

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000240

Gnomad OTH exome

AF:

0.00164

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00197

AC:

2880

AN:

1460808

Hom.:

AF XY:

0.00170

AC XY:

1236

AN XY:

726696

show subpopulations

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

African (AFR)

AF:

0.0619

AC:

2061

AN:

33302

American (AMR)

AF:

0.00671

AC:

300

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.000186

AC:

AN:

86224

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00243

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.000224

AC:

249

AN:

1111252

Other (OTH)

AF:

0.00396

AC:

239

AN:

60336

⚠️ 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: 0.327

Heterozygous variant carriers

198

396

595

793

991

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

216

288

360

<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:

0.0185

AC:

2815

AN:

151848

Hom.:

Cov.:

AF XY:

0.0178

AC XY:

1324

AN XY:

74230

show subpopulations

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

African (AFR)

AF:

0.0621

AC:

2556

AN:

41172

American (AMR)

AF:

0.0141

AC:

215

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.000207

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000250

AC:

AN:

67994

Other (OTH)

AF:

0.0118

AC:

AN:

2110

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 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: 0.377

Heterozygous variant carriers

127

255

382

510

637

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

102

136

170

<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:

0.000840

Hom.:

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Jan 09, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

3.1

Mutation Taster

=82/118

disease causing (fs/PTC)

(source)

Splicing

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

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over