12-27963397-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_198965.2(PTHLH):c.475G>A(p.Gly159Arg) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTHLH NM_198965.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.13

Genes affected

PTHLH (HGNC:9607): (parathyroid hormone like hormone) The protein encoded by this gene is a member of the parathyroid hormone family. This hormone, via its receptor, PTHR1, regulates endochondral bone development and epithelial-mesenchymal interactions during the formation of the mammary glands and teeth. It is responsible for most cases of humoral hypercalcemia of malignancy, and mutations in this gene are associated with brachydactyly type E2 (BDE2). Alternatively spliced transcript variants have been found for this gene. There is also evidence for alternative translation initiation from non-AUG (CUG and GUG) start sites, downstream of the initiator AUG codon, resulting in nuclear forms of this hormone. [provided by RefSeq, Nov 2013]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a chain Parathyroid hormone-related protein (size 140) in uniprot entity PTHR_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_198965.2
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08671588).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTHLH	NM_198965.2	c.475G>A	p.Gly159Arg	missense_variant	5/6	ENST00000545234.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTHLH	ENST00000545234.6	c.475G>A	p.Gly159Arg	missense_variant	5/6	5	NM_198965.2	A1
	ENST00000538113.1	n.90+4791C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

PTHLH-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 31, 2023

The PTHLH c.475G>A variant is predicted to result in the amino acid substitution p.Gly159Arg. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	17
Dann	Uncertain	1.0
DEOGEN2	Benign	0.21	T;T;T;.;.;.;.;.
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.81	T;.;.;T;T;.;.;T
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.087	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	1.8	L;L;L;L;L;L;L;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.39	N;N;N;N;N;N;N;N
REVEL	Benign	0.18
Sift	Benign	0.11	T;T;T;T;T;T;T;T
Sift4G	Benign	0.14	T;T;T;T;T;T;T;T
Polyphen		0.0010	B;B;B;.;.;.;.;.
Vest4		0.30
MutPred		0.14		Gain of sheet (P = 0.0266);Gain of sheet (P = 0.0266);Gain of sheet (P = 0.0266);Gain of sheet (P = 0.0266);Gain of sheet (P = 0.0266);Gain of sheet (P = 0.0266);Gain of sheet (P = 0.0266);Gain of sheet (P = 0.0266);
MVP		0.17
MPC		1.0
ClinPred		0.31	T
GERP RS		4.7
Varity_R		0.079
gMVP		0.069

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: rs2062778870; hg19: chr12-28116330;