12-27959323-C-T

Variant names:

• chr12-27959323-C-T
• rs10492364
• NM_198965.2:c.525-755G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_198965.2(PTHLH):​c.525-755G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.201 in 152,028 control chromosomes in the GnomAD database, including 3,610 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.20 (3610 hom., cov: 33)
• Consequence: PTHLH NM_198965.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0660
• Publications: 11 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.295 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTHLH	NM_198965.2	c.525-755G>A		intron_variant	Intron 5 of 5	ENST00000545234.6	NP_945316.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTHLH	ENST00000545234.6	c.525-755G>A		intron_variant	Intron 5 of 5	5	NM_198965.2	ENSP00000441765.1

Frequencies

GnomAD3 genomes AF: 0.201 AC: 30487 AN: 151910 Hom.: 3604 Cov.: 33

Gnomad AFR AF: 0.0743

Gnomad AMI AF: 0.284

Gnomad AMR AF: 0.209

Gnomad ASJ AF: 0.184

Gnomad EAS AF: 0.308

Gnomad SAS AF: 0.240

Gnomad FIN AF: 0.349

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.242

Gnomad OTH AF: 0.182

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.201 AC: 30513 AN: 152028 Hom.: 3610 Cov.: 33 AF XY: 0.205 AC XY: 15221 AN XY: 74312

African (AFR) AF: 0.0743 AC: 3081 AN: 41488

American (AMR) AF: 0.210 AC: 3208 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.184 AC: 637 AN: 3468

East Asian (EAS) AF: 0.308 AC: 1589 AN: 5158

South Asian (SAS) AF: 0.240 AC: 1155 AN: 4818

European-Finnish (FIN) AF: 0.349 AC: 3679 AN: 10546

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.242 AC: 16462 AN: 67966

Other (OTH) AF: 0.184 AC: 388 AN: 2110

Alfa AF: 0.218 Hom.: 3711

Bravo AF: 0.186

Asia WGS AF: 0.256 AC: 890 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.0
DANN	Benign	0.60
PhyloP100		-0.066
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs10492364; hg19: chr12-28112256; COSMIC: COSV52367594; COSMIC: COSV52367594;