12-27963441-C-T

Variant names:

• chr12-27963441-C-T
• NM_198965.2:c.431G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_198965.2(PTHLH):​c.431G>A​(p.Arg144His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R144G) has been classified 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: 6.96
• Publications: 0 publications found

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

ENSG00000257042 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTHLH	NM_198965.2	MANE Select	c.431G>A	p.Arg144His	missense	Exon 5 of 6	NP_945316.1	P12272-1
	PTHLH	NM_198966.2		c.431G>A	p.Arg144His	missense	Exon 3 of 4	NP_945317.1	P12272-1
	PTHLH	NM_002820.3		c.431G>A	p.Arg144His	missense	Exon 4 of 4	NP_002811.1	P12272-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTHLH	ENST00000545234.6	TSL:5 MANE Select	c.431G>A	p.Arg144His	missense	Exon 5 of 6	ENSP00000441765.1	P12272-1
	PTHLH	ENST00000395868.7	TSL:1	c.431G>A	p.Arg144His	missense	Exon 3 of 3	ENSP00000379209.3	P12272-2
	PTHLH	ENST00000535992.5	TSL:1	c.431G>A	p.Arg144His	missense	Exon 3 of 3	ENSP00000440613.1	P12272-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.61	D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.35	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		7.0
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-2.6	D
REVEL	Pathogenic	0.65
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.78
MutPred		0.30		Loss of MoRF binding (P = 0.0688)
MVP		0.82
MPC		1.9
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.48
gMVP		0.62
Mutation Taster		=55/45	polymorphism

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

Other links and lift over

hg19: chr12-28116374;