Genetic Variant PTHLH:p.Gly159Arg (chr12-27963397-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_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. 16/22 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

PTHLH
NM_198965.2 missense

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 3.13

Publications

0 publications found

Variant links:

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]

PTHLH Gene-Disease associations (from GenCC):

brachydactyly type E2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
brachydactyly type E
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

PTHLH links:

ENSG00000257042 (HGNC:):

ENSG00000257042 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08671588).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198965.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PTHLH	NM_198965.2	MANE Select	c.475G>A	p.Gly159Arg	missense	Exon 5 of 6	NP_945316.1	P12272-1
PTHLH	NM_198966.2		c.475G>A	p.Gly159Arg	missense	Exon 3 of 4	NP_945317.1	P12272-1
PTHLH	NM_002820.3		c.475G>A	p.Gly159Arg	missense	Exon 4 of 4	NP_002811.1	P12272-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PTHLH	ENST00000545234.6	TSL:5 MANE Select	c.475G>A	p.Gly159Arg	missense	Exon 5 of 6	ENSP00000441765.1	P12272-1
PTHLH	ENST00000395868.7	TSL:1	c.475G>A	p.Gly159Arg	missense	Exon 3 of 3	ENSP00000379209.3	P12272-2
PTHLH	ENST00000535992.5	TSL:1	c.475G>A	p.Gly159Arg	missense	Exon 3 of 3	ENSP00000440613.1	P12272-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

PTHLH-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.33

FATHMM_MKL

Benign

0.38

LIST_S2

Benign

0.81

M_CAP

Benign

0.046

MetaRNN

Benign

0.087

MetaSVM

Benign

-0.47

MutationAssessor

Benign

1.8

PhyloP100

3.1

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.39

REVEL

Benign

0.18

Sift

Benign

0.11

Sift4G

Benign

0.14

Polyphen

0.0010

Vest4

0.30

MutPred

0.14

Gain of sheet (P = 0.0266)

MVP

0.17

MPC

1.0

ClinPred

0.31

GERP RS

4.7

Varity_R

0.079

gMVP

0.069

Mutation Taster

=82/18

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over