chr12-27958568-C-T

Position:

• chr12-27958568-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_198965.2(PTHLH):​c.525G>A​(p.Arg175Arg) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.000000704 in 1,420,002 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: PTHLH NM_198965.2 splice_region, synonymous
• Scores: Splicing: ADA: 0.9898
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.17

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]

ENSG00000257042 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTHLH	NM_198965.2	c.525G>A	p.Arg175Arg	splice_region_variant, synonymous_variant	6/6	ENST00000545234.6	NP_945316.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTHLH	ENST00000545234.6	c.525G>A	p.Arg175Arg	splice_region_variant, synonymous_variant	6/6	5	NM_198965.2	ENSP00000441765.1
PTHLH	ENST00000395872.5	c.525G>A	p.Arg175Arg	splice_region_variant, synonymous_variant	5/5	5		ENSP00000379213.1
PTHLH	ENST00000539239.5	c.525G>A	p.Arg175Arg	splice_region_variant, synonymous_variant	3/3	5		ENSP00000441571.1
ENSG00000257042	ENST00000538113.1	n.52C>T		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.04e-7 AC: 1 AN: 1420002 Hom.: 0 Cov.: 29 AF XY: 0.00000142 AC XY: 1 AN XY: 702350

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: 9.18e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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

Labcorp Genetics (formerly Invitae), Labcorp

Aug 06, 2023

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 sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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 affects codon 175 of the PTHLH mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the PTHLH protein. It affects a nucleotide within the consensus splice site. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	22
DANN	Benign	0.87

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Benign	0.67

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

Publications

LitVar

Other links and lift over

dbSNP: rs2062729969; hg19: chr12-28111501;