rs104894272

Positions:

• chr11-13492789-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The ENST00000282091.6(PTH):​c.67T>C​(p.Ser23Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. S23S) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTH ENST00000282091.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: -0.359

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 11-13492789-A-G is Pathogenic according to our data. Variant chr11-13492789-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 13758.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTH	NM_000315.4	c.67T>C	p.Ser23Pro	missense_variant	2/3	ENST00000282091.6	NP_000306.1
PTH	NM_001316352.2	c.163T>C	p.Ser55Pro	missense_variant	2/3		NP_001303281.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTH	ENST00000282091.6	c.67T>C	p.Ser23Pro	missense_variant	2/3	1	NM_000315.4	ENSP00000282091	P1
PTH	ENST00000529816.1	c.67T>C	p.Ser23Pro	missense_variant	2/3	5		ENSP00000433208	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hypoparathyroidism, familial isolated 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 1999

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.097	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Uncertain	0.48	T;T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.064	N
LIST_S2	Benign	0.60	.;T
M_CAP	Benign	0.033	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Benign	-0.69	T
MutationAssessor	Uncertain	2.1	M;M
MutationTaster	Benign	9.2e-11	A;A
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.3	N;N
REVEL	Uncertain	0.59
Sift	Benign	0.22	T;T
Sift4G	Benign	0.16	T;T
Polyphen		0.55	P;P
Vest4		0.83
MutPred		0.81		Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);
MVP		0.83
MPC		0.49
ClinPred		0.31	T
GERP RS		-1.6
Varity_R		0.12
gMVP		0.30

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

LitVar

Other links and lift over

dbSNP: rs104894272; hg19: chr11-13514336;