Genetic Variant NM_004219.4:c.276+91C>T (chr5-160422984-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_004219.4(PTTG1):c.276+91C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.269 in 1,351,732 control chromosomes in the GnomAD database, including 51,136 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.23 ( 4679 hom., cov: 33)

Exomes 𝑓: 0.27 ( 46457 hom. )

Consequence

PTTG1
NM_004219.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.494

Publications

8 publications found

Variant links:

Genes affected

PTTG1 (HGNC:9690): (PTTG1 regulator of sister chromatid separation, securin) The encoded protein is a homolog of yeast securin proteins, which prevent separins from promoting sister chromatid separation. It is an anaphase-promoting complex (APC) substrate that associates with a separin until activation of the APC. The gene product has transforming activity in vitro and tumorigenic activity in vivo, and the gene is highly expressed in various tumors. The gene product contains 2 PXXP motifs, which are required for its transforming and tumorigenic activities, as well as for its stimulation of basic fibroblast growth factor expression. It also contains a destruction box (D box) that is required for its degradation by the APC. The acidic C-terminal region of the encoded protein can act as a transactivation domain. The gene product is mainly a cytosolic protein, although it partially localizes in the nucleus. Three transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Sep 2013]

PTTG1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.306 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
PTTG1	NM_004219.4 link	c.276+91C>T	intron_variant	Intron 3 of 5	ENST00000352433.10	NP_004210.1	O95997Q6IAL9
PTTG1	NM_001282382.1 link	c.276+91C>T	intron_variant	Intron 2 of 4		NP_001269311.1	O95997Q6IAL9
PTTG1	NM_001282383.1 link	c.276+91C>T	intron_variant	Intron 3 of 5		NP_001269312.1	O95997Q6IAL9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTTG1	ENST00000352433.10 link	c.276+91C>T		intron_variant	Intron 3 of 5	1	NM_004219.4	ENSP00000344936.5		O95997

Frequencies

GnomAD3 genomes

AF:

0.234

AC:

35568

AN:

152078

Hom.:

4674

Cov.:

show subpopulations

Gnomad AFR

AF:

0.133

Gnomad AMI

AF:

0.218

Gnomad AMR

AF:

0.313

Gnomad ASJ

AF:

0.294

Gnomad EAS

AF:

0.124

Gnomad SAS

AF:

0.307

Gnomad FIN

AF:

0.251

Gnomad MID

AF:

0.171

Gnomad NFE

AF:

0.276

Gnomad OTH

AF:

0.222

GnomAD4 exome

AF:

0.273

AC:

327733

AN:

1199534

Hom.:

46457

Cov.:

AF XY:

0.274

AC XY:

165665

AN XY:

603828

show subpopulations

African (AFR)

AF:

0.122

AC:

3284

AN:

26864

American (AMR)

AF:

0.384

AC:

13663

AN:

35624

Ashkenazi Jewish (ASJ)

AF:

0.291

AC:

6268

AN:

21568

East Asian (EAS)

AF:

0.154

AC:

5796

AN:

37746

South Asian (SAS)

AF:

0.326

AC:

23257

AN:

71328

European-Finnish (FIN)

AF:

0.263

AC:

13162

AN:

50078

Middle Eastern (MID)

AF:

0.227

AC:

1164

AN:

5124

European-Non Finnish (NFE)

AF:

0.276

AC:

248409

AN:

900016

Other (OTH)

AF:

0.249

AC:

12730

AN:

51186

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

11572

23145

34717

46290

57862

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7742

15484

23226

30968

38710

<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:

0.234

AC:

35599

AN:

152198

Hom.:

4679

Cov.:

AF XY:

0.235

AC XY:

17459

AN XY:

74404

show subpopulations

African (AFR)

AF:

0.133

AC:

5538

AN:

41548

American (AMR)

AF:

0.314

AC:

4797

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.294

AC:

1021

AN:

3470

East Asian (EAS)

AF:

0.124

AC:

644

AN:

5174

South Asian (SAS)

AF:

0.307

AC:

1480

AN:

4826

European-Finnish (FIN)

AF:

0.251

AC:

2654

AN:

10582

Middle Eastern (MID)

AF:

0.170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.276

AC:

18747

AN:

67996

Other (OTH)

AF:

0.223

AC:

470

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1370

2739

4109

5478

6848

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

382

764

1146

1528

1910

<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:

0.271

Hom.:

2998

Bravo

AF:

0.232

Asia WGS

AF:

0.199

AC:

694

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

7.8

(source)

DANN

Benign

0.75

PhyloP100

-0.49

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over