12-27958568-C-T

Variant names:

• chr12-27958568-C-T
• rs2062729969
• NM_198965.2:c.525G>A

Variant summary

Our verdict is Uncertain significance. The variant received 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
• 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.525G>A	p.Arg175Arg	splice_region synonymous	Exon 6 of 6	NP_945316.1	P12272-1
	PTHLH	NM_198966.2		c.525G>A	p.Arg175Arg	splice_region synonymous	Exon 4 of 4	NP_945317.1	P12272-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTHLH	ENST00000545234.6	TSL:5 MANE Select	c.525G>A	p.Arg175Arg	splice_region synonymous	Exon 6 of 6	ENSP00000441765.1	P12272-1
	PTHLH	ENST00000395872.5	TSL:5	c.525G>A	p.Arg175Arg	splice_region synonymous	Exon 5 of 5	ENSP00000379213.1	P12272-1
	PTHLH	ENST00000539239.5	TSL:5	c.525G>A	p.Arg175Arg	splice_region synonymous	Exon 3 of 3	ENSP00000441571.1	P12272-1

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32524

American (AMR) AF: 0.00 AC: 0 AN: 39120

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25354

East Asian (EAS) AF: 0.00 AC: 0 AN: 38246

South Asian (SAS) AF: 0.00 AC: 0 AN: 80260

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50922

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5708

European-Non Finnish (NFE) AF: 9.18e-7 AC: 1 AN: 1089026

Other (OTH) AF: 0.00 AC: 0 AN: 58842

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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
BayesDel_noAF	Benign	-0.31
CADD	Benign	22
DANN	Benign	0.87
PhyloP100		4.2

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

Other links and lift over

dbSNP: rs2062729969; hg19: chr12-28111501;