dbSNP rs6254: PTH:c.87-50G>A (chr11-13492716-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000315.4(PTH):c.87-50G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.316 in 1,613,372 control chromosomes in the GnomAD database, including 85,603 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.26 ( 6236 hom., cov: 32)

Exomes 𝑓: 0.32 ( 79367 hom. )

Consequence

PTH
NM_000315.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.298

Publications

27 publications found

Variant links:

Genes affected

PTH (HGNC:9606): (parathyroid hormone) This gene encodes a member of the parathyroid family of proteins. The encoded preproprotein is proteolytically processed to generate a protein that binds to the parathyroid hormone/parathyroid hormone-related peptide receptor and regulates blood calcium and phosphate levels. Excess production of the encoded protein, known as hyperparathyroidism, can result in hypercalcemia and kidney stones. On the other hand, defective processing of the encoded protein may lead to hypoparathyroidism, which can result in hypocalcemia and numbness. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2015]

PTH Gene-Disease associations (from GenCC):

hypoparathyroidism, familial isolated 1
Inheritance: AD, AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
familial isolated hypoparathyroidism due to impaired PTH secretion
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

PTH links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 11-13492716-C-T is Benign according to our data. Variant chr11-13492716-C-T is described in ClinVar as Benign. ClinVar VariationId is 1289830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.348 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000315.4. 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
	PTH	NM_000315.4	MANE Select	c.87-50G>A		intron	N/A	NP_000306.1	P01270
	PTH	NM_001316352.2		c.183-50G>A		intron	N/A	NP_001303281.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTH	ENST00000282091.6	TSL:1 MANE Select	c.87-50G>A		intron	N/A	ENSP00000282091.1	P01270
	PTH	ENST00000529816.1	TSL:5	c.87-50G>A		intron	N/A	ENSP00000433208.1	P01270

Frequencies

GnomAD3 genomes

AF:

0.261

AC:

39613

AN:

151932

Hom.:

6240

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0929

Gnomad AMI

AF:

0.332

Gnomad AMR

AF:

0.259

Gnomad ASJ

AF:

0.299

Gnomad EAS

AF:

0.117

Gnomad SAS

AF:

0.194

Gnomad FIN

AF:

0.421

Gnomad MID

AF:

0.275

Gnomad NFE

AF:

0.351

Gnomad OTH

AF:

0.260

GnomAD2 exomes

AF:

0.283

AC:

70884

AN:

250436

AF XY:

0.286

show subpopulations

Gnomad AFR exome

AF:

0.0871

Gnomad AMR exome

AF:

0.221

Gnomad ASJ exome

AF:

0.304

Gnomad EAS exome

AF:

0.116

Gnomad FIN exome

AF:

0.412

Gnomad NFE exome

AF:

0.354

Gnomad OTH exome

AF:

0.314

GnomAD4 exome

AF:

0.321

AC:

469593

AN:

1461322

Hom.:

79367

Cov.:

AF XY:

0.319

AC XY:

231828

AN XY:

726924

show subpopulations

African (AFR)

AF:

0.0820

AC:

2746

AN:

33474

American (AMR)

AF:

0.224

AC:

9990

AN:

44594

Ashkenazi Jewish (ASJ)

AF:

0.302

AC:

7894

AN:

26128

East Asian (EAS)

AF:

0.104

AC:

4139

AN:

39694

South Asian (SAS)

AF:

0.195

AC:

16777

AN:

86240

European-Finnish (FIN)

AF:

0.402

AC:

21461

AN:

53364

Middle Eastern (MID)

AF:

0.272

AC:

1568

AN:

5768

European-Non Finnish (NFE)

AF:

0.348

AC:

387251

AN:

1111694

Other (OTH)

AF:

0.294

AC:

17767

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

19407

38814

58221

77628

97035

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12012

24024

36036

48048

60060

<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:

0.261

AC:

39612

AN:

152050

Hom.:

6236

Cov.:

AF XY:

0.261

AC XY:

19398

AN XY:

74316

show subpopulations

African (AFR)

AF:

0.0929

AC:

3855

AN:

41510

American (AMR)

AF:

0.258

AC:

3944

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.299

AC:

1038

AN:

3470

East Asian (EAS)

AF:

0.117

AC:

603

AN:

5168

South Asian (SAS)

AF:

0.194

AC:

936

AN:

4822

European-Finnish (FIN)

AF:

0.421

AC:

4440

AN:

10538

Middle Eastern (MID)

AF:

0.265

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.351

AC:

23874

AN:

67970

Other (OTH)

AF:

0.257

AC:

542

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1373

2745

4118

5490

6863

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

404

808

1212

1616

2020

<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:

0.304

Hom.:

22516

Bravo

AF:

0.241

Asia WGS

AF:

0.156

AC:

543

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

6.6

(source)

DANN

Benign

0.60

PhyloP100

-0.30

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over