Genetic Variant NM_000315.4:c.-5-10G>A (chr11-13492870-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.-5-10G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.594 in 1,606,000 control chromosomes in the GnomAD database, including 292,652 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.51 ( 21695 hom., cov: 32)

Exomes 𝑓: 0.60 ( 270957 hom. )

Consequence

PTH
NM_000315.4 intron

Scores

Splicing: ADA: 0.0001624

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.866

Publications

20 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=-0.83).

BP6

Variant 11-13492870-C-T is Benign according to our data. Variant chr11-13492870-C-T is described in ClinVar as Benign. ClinVar VariationId is 255816.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.635 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.-5-10G>A		intron	N/A	NP_000306.1	P01270
	PTH	NM_001316352.2		c.92-10G>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.-5-10G>A		intron	N/A	ENSP00000282091.1	P01270
	PTH	ENST00000529816.1	TSL:5	c.-5-10G>A		intron	N/A	ENSP00000433208.1	P01270

Frequencies

GnomAD3 genomes

AF:

0.507

AC:

76837

AN:

151662

Hom.:

21692

Cov.:

show subpopulations

Gnomad AFR

AF:

0.262

Gnomad AMI

AF:

0.526

Gnomad AMR

AF:

0.481

Gnomad ASJ

AF:

0.699

Gnomad EAS

AF:

0.301

Gnomad SAS

AF:

0.590

Gnomad FIN

AF:

0.631

Gnomad MID

AF:

0.679

Gnomad NFE

AF:

0.640

Gnomad OTH

AF:

0.526

GnomAD2 exomes

AF:

0.546

AC:

135527

AN:

248030

AF XY:

0.564

show subpopulations

Gnomad AFR exome

AF:

0.252

Gnomad AMR exome

AF:

0.367

Gnomad ASJ exome

AF:

0.700

Gnomad EAS exome

AF:

0.296

Gnomad FIN exome

AF:

0.621

Gnomad NFE exome

AF:

0.640

Gnomad OTH exome

AF:

0.600

GnomAD4 exome

AF:

0.603

AC:

877199

AN:

1454218

Hom.:

270957

Cov.:

AF XY:

0.606

AC XY:

438607

AN XY:

723802

show subpopulations

African (AFR)

AF:

0.254

AC:

8447

AN:

33200

American (AMR)

AF:

0.379

AC:

16883

AN:

44506

Ashkenazi Jewish (ASJ)

AF:

0.699

AC:

18251

AN:

26092

East Asian (EAS)

AF:

0.293

AC:

11583

AN:

39584

South Asian (SAS)

AF:

0.599

AC:

51523

AN:

85978

European-Finnish (FIN)

AF:

0.623

AC:

33200

AN:

53248

Middle Eastern (MID)

AF:

0.626

AC:

3449

AN:

5508

European-Non Finnish (NFE)

AF:

0.632

AC:

698880

AN:

1106054

Other (OTH)

AF:

0.583

AC:

34983

AN:

60048

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

17027

34055

51082

68110

85137

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18242

36484

54726

72968

91210

<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:

0.506

AC:

76858

AN:

151782

Hom.:

21695

Cov.:

AF XY:

0.508

AC XY:

37708

AN XY:

74202

show subpopulations

African (AFR)

AF:

0.262

AC:

10825

AN:

41374

American (AMR)

AF:

0.481

AC:

7327

AN:

15238

Ashkenazi Jewish (ASJ)

AF:

0.699

AC:

2424

AN:

3468

East Asian (EAS)

AF:

0.301

AC:

1552

AN:

5148

South Asian (SAS)

AF:

0.591

AC:

2845

AN:

4814

European-Finnish (FIN)

AF:

0.631

AC:

6633

AN:

10512

Middle Eastern (MID)

AF:

0.679

AC:

197

AN:

290

European-Non Finnish (NFE)

AF:

0.640

AC:

43469

AN:

67918

Other (OTH)

AF:

0.525

AC:

1107

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1746

3492

5237

6983

8729

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

672

1344

2016

2688

3360

<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:

0.571

Hom.:

5543

Bravo

AF:

0.478

Asia WGS

AF:

0.447

AC:

1555

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

Familial hypoparathyroidism (1)

Hypoparathyroidism, familial isolated 1 (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

(source)

DANN

Benign

0.33

PhyloP100

0.87

Mutation Taster

=8/92

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00016

dbscSNV1_RF

Benign

0.0020

SpliceAI score (max)

0.020

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