chr11-13492804-A-G

Variant names:

• chr11-13492804-A-G
• rs104894271
• NM_000315.4:c.52T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_000315.4(PTH):​c.52T>C​(p.Cys18Arg) 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. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTH NM_000315.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.14
• Publications: 13 publications found

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979
• PP5: Variant 11-13492804-A-G is Pathogenic according to our data. Variant chr11-13492804-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 13756.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTH	NM_000315.4	c.52T>C	p.Cys18Arg	missense_variant	Exon 2 of 3	ENST00000282091.6	NP_000306.1
PTH	NM_001316352.2	c.148T>C	p.Cys50Arg	missense_variant	Exon 2 of 3		NP_001303281.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTH	ENST00000282091.6	c.52T>C	p.Cys18Arg	missense_variant	Exon 2 of 3	1	NM_000315.4	ENSP00000282091.1
PTH	ENST00000529816.1	c.52T>C	p.Cys18Arg	missense_variant	Exon 2 of 3	5		ENSP00000433208.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hypoparathyroidism, familial isolated 1 Pathogenic:1

Dec 11, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.17
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.79	D;D
Eigen	Benign	0.14
Eigen_PC	Benign	0.15
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.47	.;T
M_CAP	Benign	0.061	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	0.31	D
MutationAssessor	Uncertain	2.5	M;M
PhyloP100		1.1
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-3.5	D;D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.027	D;D
Sift4G	Benign	0.11	T;T
Polyphen		0.74	P;P
Vest4		0.90
MutPred		0.91		Gain of MoRF binding (P = 4e-04);Gain of MoRF binding (P = 4e-04);
MVP		0.97
MPC		0.72
ClinPred		0.89	D
GERP RS		4.8
Varity_R		0.66
gMVP		0.63
Mutation Taster		=6/94	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs104894271; hg19: chr11-13514351;