dbSNP rs1805777: PHC1:p.Arg306Arg (chr12-8930740-A-G) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_004426.3(PHC1):c.918A>G(p.Arg306Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.86 ( 54764 hom., cov: 20)

Exomes 𝑓: 0.93 ( 467421 hom. )

Failed GnomAD Quality Control

Consequence

PHC1
NM_004426.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 3.08

Publications

11 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: G2P, Labcorp Genetics (formerly Invitae)

PHC1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.59).

BP6

Variant 12-8930740-A-G is Benign according to our data. Variant chr12-8930740-A-G is described in ClinVar as Benign. ClinVar VariationId is 211899.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=3.08 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.94 is higher than 0.05.

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	UniProt
PHC1	NM_004426.3	MANE Select	c.918A>G	p.Arg306Arg	synonymous	Exon 7 of 15	NP_004417.2	P78364
PHC1	NM_001413738.1		c.918A>G	p.Arg306Arg	synonymous	Exon 7 of 15	NP_001400667.1	P78364
PHC1	NM_001413739.1		c.912A>G	p.Arg304Arg	synonymous	Exon 7 of 15	NP_001400668.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PHC1	ENST00000544916.6	TSL:1 MANE Select	c.918A>G	p.Arg306Arg	synonymous	Exon 7 of 15	ENSP00000437659.1	P78364
PHC1	ENST00000543824.5	TSL:1	c.918A>G	p.Arg306Arg	synonymous	Exon 8 of 16	ENSP00000440674.1	P78364
PHC1	ENST00000433083.6	TSL:1	c.783A>G	p.Arg261Arg	synonymous	Exon 6 of 14	ENSP00000399194.2	J3KQH6

Frequencies

GnomAD3 genomes

AF:

0.855

AC:

124731

AN:

145816

Hom.:

54741

Cov.:

show subpopulations

Gnomad AFR

AF:

0.645

Gnomad AMI

AF:

0.950

Gnomad AMR

AF:

0.900

Gnomad ASJ

AF:

0.942

Gnomad EAS

AF:

0.782

Gnomad SAS

AF:

0.964

Gnomad FIN

AF:

0.968

Gnomad MID

AF:

0.916

Gnomad NFE

AF:

0.946

Gnomad OTH

AF:

0.858

GnomAD2 exomes

AF:

0.860

AC:

107968

AN:

125610

AF XY:

0.870

show subpopulations

Gnomad AFR exome

AF:

0.482

Gnomad AMR exome

AF:

0.900

Gnomad ASJ exome

AF:

0.864

Gnomad EAS exome

AF:

0.717

Gnomad FIN exome

AF:

0.945

Gnomad NFE exome

AF:

0.901

Gnomad OTH exome

AF:

0.893

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.933

AC:

972484

AN:

1042370

Hom.:

467421

Cov.:

AF XY:

0.934

AC XY:

484419

AN XY:

518604

show subpopulations

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

African (AFR)

AF:

0.585

AC:

13794

AN:

23582

American (AMR)

AF:

0.896

AC:

24366

AN:

27196

Ashkenazi Jewish (ASJ)

AF:

0.917

AC:

17694

AN:

19306

East Asian (EAS)

AF:

0.767

AC:

26283

AN:

34256

South Asian (SAS)

AF:

0.964

AC:

60175

AN:

62428

European-Finnish (FIN)

AF:

0.958

AC:

44558

AN:

46494

Middle Eastern (MID)

AF:

0.906

AC:

3367

AN:

3718

European-Non Finnish (NFE)

AF:

0.950

AC:

741018

AN:

780126

Other (OTH)

AF:

0.911

AC:

41229

AN:

45264

⚠️ 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: 0.343

Heterozygous variant carriers

2035

4070

6104

8139

10174

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13556

27112

40668

54224

67780

<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:

0.855

AC:

124800

AN:

145932

Hom.:

54764

Cov.:

AF XY:

0.855

AC XY:

60498

AN XY:

70748

show subpopulations

African (AFR)

AF:

0.644

AC:

25365

AN:

39360

American (AMR)

AF:

0.900

AC:

12964

AN:

14398

Ashkenazi Jewish (ASJ)

AF:

0.942

AC:

3207

AN:

3406

East Asian (EAS)

AF:

0.783

AC:

3892

AN:

4970

South Asian (SAS)

AF:

0.964

AC:

4118

AN:

4272

European-Finnish (FIN)

AF:

0.968

AC:

9535

AN:

9848

Middle Eastern (MID)

AF:

0.920

AC:

265

AN:

288

European-Non Finnish (NFE)

AF:

0.946

AC:

62925

AN:

66538

Other (OTH)

AF:

0.858

AC:

1682

AN:

1960

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.406

Heterozygous variant carriers

695

1390

2084

2779

3474

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

832

1664

2496

3328

4160

<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:

0.893

Hom.:

10459

Bravo

AF:

0.841

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Microcephaly 11, primary, autosomal recessive (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.59

CADD

Benign

(source)

DANN

Benign

0.64

PhyloP100

3.1

PromoterAI

-0.011

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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

Computational scores

Splicing

Publications

Other links and lift over