12-27958559-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_198965.2(PTHLH):c.534A>G(p.Ter178TrpextTer53) variant causes a stop lost 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. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PTHLH NM_198965.2 stop_lost
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.44

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.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-27958559-T-C is Pathogenic according to our data. Variant chr12-27958559-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 13740.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr12-27958559-T-C is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (BayesDel_addAF=0.00764496).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTHLH	NM_198965.2	c.534A>G	p.Ter178TrpextTer53	stop_lost	6/6	ENST00000545234.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTHLH	ENST00000545234.6	c.534A>G	p.Ter178TrpextTer53	stop_lost	6/6	5	NM_198965.2	A1
	ENST00000538113.1	n.43T>C		non_coding_transcript_exon_variant	1/2	3
PTHLH	ENST00000395872.5	c.534A>G	p.Ter178TrpextTer53	stop_lost	5/5	5		A1
PTHLH	ENST00000539239.5	c.534A>G	p.Ter178TrpextTer53	stop_lost	3/3	5		A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Brachydactyly type E2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 12, 2010

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	0.0076	T
BayesDel_noAF	Benign	-0.23
Cadd	Benign	19
Dann	Benign	0.92
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Uncertain	0.86	D
MutationTaster	Benign	1.0	N;N;N
Vest4		0.26
GERP RS		5.6

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs267606987; hg19: chr12-28111492;