11-13492453-C-A

Position:

• chr11-13492453-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000315.4(PTH):​c.300G>T​(p.Glu100Asp) 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 benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTH NM_000315.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: -0.0120

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.122556746).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTH	NM_000315.4	c.300G>T	p.Glu100Asp	missense_variant	3/3	ENST00000282091.6
PTH	NM_001316352.2	c.396G>T	p.Glu132Asp	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTH	ENST00000282091.6	c.300G>T	p.Glu100Asp	missense_variant	3/3	1	NM_000315.4	P1
PTH	ENST00000529816.1	c.300G>T	p.Glu100Asp	missense_variant	3/3	5		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Martin Pollak Laboratory, Beth Israel Deaconess Medical Center

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.083	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T;T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.75	.;T
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.12	T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Uncertain	2.3	M;M
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.58	N;N
REVEL	Benign	0.16
Sift	Benign	0.14	T;T
Sift4G	Benign	0.18	T;T
Polyphen		0.21	B;B
Vest4		0.066
MutPred		0.61		Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);
MVP		0.86
MPC		0.88
ClinPred		0.45	T
GERP RS		0.55
Varity_R		0.058
gMVP		0.057

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: rs387907455; hg19: chr11-13514000;