12-27963369-G-A

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.503C>T(p.Thr168Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: PTHLH NM_198965.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.89

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=0.16408387).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTHLH	NM_198965.2	c.503C>T	p.Thr168Met	missense_variant	5/6	ENST00000545234.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTHLH	ENST00000545234.6	c.503C>T	p.Thr168Met	missense_variant	5/6	5	NM_198965.2	A1
	ENST00000538113.1	n.90+4763G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461890 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 25, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with PTHLH-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 168 of the PTHLH protein (p.Thr168Met). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.083	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	19
Dann	Uncertain	1.0
DEOGEN2	Benign	0.33	T;T;T;.;.;.;.;.
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.82	T;.;.;T;T;.;.;T
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.16	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.31	T
MutationAssessor	Uncertain	2.1	M;M;M;M;M;M;M;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.83	N;N;N;N;N;N;N;N
REVEL	Benign	0.20
Sift	Uncertain	0.0020	D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0090	D;D;D;D;D;D;D;D
Polyphen		0.10	B;B;B;.;.;.;.;.
Vest4		0.25
MutPred		0.18		Loss of glycosylation at T168 (P = 0.0234);Loss of glycosylation at T168 (P = 0.0234);Loss of glycosylation at T168 (P = 0.0234);Loss of glycosylation at T168 (P = 0.0234);Loss of glycosylation at T168 (P = 0.0234);Loss of glycosylation at T168 (P = 0.0234);Loss of glycosylation at T168 (P = 0.0234);Loss of glycosylation at T168 (P = 0.0234);
MVP		0.38
MPC		0.73
ClinPred		0.67	D
GERP RS		4.7
Varity_R		0.069
gMVP		0.20

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: rs1463175258; hg19: chr12-28116302; COSMIC: COSV52366518; COSMIC: COSV52366518;