dbSNP rs16912873: PTH:c.*319A>G (chr11-13492086-T-C) – 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.*319A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0198 in 301,604 control chromosomes in the GnomAD database, including 332 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.035 ( 302 hom., cov: 32)

Exomes 𝑓: 0.0040 ( 30 hom. )

Consequence

PTH
NM_000315.4 3_prime_UTR

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.415

Publications

1 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=-0.75).

BP6

Variant 11-13492086-T-C is Benign according to our data. Variant chr11-13492086-T-C is described in ClinVar as Benign. ClinVar VariationId is 303700.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.118 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.*319A>G		3_prime_UTR	Exon 3 of 3	NP_000306.1	P01270
	PTH	NM_001316352.2		c.*319A>G		3_prime_UTR	Exon 3 of 3	NP_001303281.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTH	ENST00000282091.6	TSL:1 MANE Select	c.*319A>G		3_prime_UTR	Exon 3 of 3	ENSP00000282091.1	P01270
	PTH	ENST00000529816.1	TSL:5	c.*319A>G		downstream_gene	N/A	ENSP00000433208.1	P01270

Frequencies

GnomAD3 genomes

AF:

0.0351

AC:

5336

AN:

152196

Hom.:

301

Cov.:

show subpopulations

Gnomad AFR

AF:

0.121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0151

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000529

Gnomad OTH

AF:

0.0277

GnomAD4 exome

AF:

0.00402

AC:

600

AN:

149290

Hom.:

Cov.:

AF XY:

0.00329

AC XY:

262

AN XY:

79532

show subpopulations

African (AFR)

AF:

0.112

AC:

455

AN:

4066

American (AMR)

AF:

0.0104

AC:

AN:

5560

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

4240

East Asian (EAS)

AF:

0.00

AC:

AN:

7058

South Asian (SAS)

AF:

0.000390

AC:

AN:

20490

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6980

Middle Eastern (MID)

AF:

0.0106

AC:

AN:

568

European-Non Finnish (NFE)

AF:

0.000174

AC:

AN:

92182

Other (OTH)

AF:

0.00700

AC:

AN:

8146

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

106

132

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.0352

AC:

5359

AN:

152314

Hom.:

302

Cov.:

AF XY:

0.0338

AC XY:

2521

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.121

AC:

5029

AN:

41542

American (AMR)

AF:

0.0151

AC:

231

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000414

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000529

AC:

AN:

68030

Other (OTH)

AF:

0.0274

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

246

492

738

984

1230

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

116

174

232

290

<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:

0.00997

Hom.:

Bravo

AF:

0.0398

Asia WGS

AF:

0.00752

AC:

AN:

3472

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Familial hypoparathyroidism (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

7.1

(source)

DANN

Benign

0.83

PhyloP100

0.41

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over