rs805512

Variant names:

• chr12-27965914-C-A
• rs805512
• NM_198965.2:c.102-2144G>T

Your query was ambiguous. Multiple possible variants found:

• chr12-27965914-C-A
• chr12-27965914-C-G
• chr12-27965914-C-T

Variant summary

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

The NM_198965.2(PTHLH):​c.102-2144G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.668 in 152,132 control chromosomes in the GnomAD database, including 34,116 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 0.67 (34116 hom., cov: 33)
• Consequence: PTHLH NM_198965.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.653
• Publications: 6 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=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.727 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTHLH	NM_198965.2	c.102-2144G>T		intron_variant	Intron 4 of 5	ENST00000545234.6	NP_945316.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTHLH	ENST00000545234.6	c.102-2144G>T		intron_variant	Intron 4 of 5	5	NM_198965.2	ENSP00000441765.1

Frequencies

GnomAD3 genomes AF: 0.668 AC: 101554 AN: 152014 Hom.: 34075 Cov.: 33

Gnomad AFR AF: 0.734

Gnomad AMI AF: 0.616

Gnomad AMR AF: 0.643

Gnomad ASJ AF: 0.659

Gnomad EAS AF: 0.737

Gnomad SAS AF: 0.672

Gnomad FIN AF: 0.671

Gnomad MID AF: 0.631

Gnomad NFE AF: 0.630

Gnomad OTH AF: 0.645

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

GnomAD4 genome AF: 0.668 AC: 101655 AN: 152132 Hom.: 34116 Cov.: 33 AF XY: 0.668 AC XY: 49701 AN XY: 74362

African (AFR) AF: 0.734 AC: 30462 AN: 41512

American (AMR) AF: 0.643 AC: 9830 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.659 AC: 2285 AN: 3466

East Asian (EAS) AF: 0.736 AC: 3815 AN: 5182

South Asian (SAS) AF: 0.671 AC: 3242 AN: 4830

European-Finnish (FIN) AF: 0.671 AC: 7085 AN: 10556

Middle Eastern (MID) AF: 0.627 AC: 183 AN: 292

European-Non Finnish (NFE) AF: 0.630 AC: 42824 AN: 67980

Other (OTH) AF: 0.647 AC: 1367 AN: 2112

Alfa AF: 0.644 Hom.: 105703

Bravo AF: 0.669

Asia WGS AF: 0.748 AC: 2600 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	11
DANN	Benign	0.70
PhyloP100		0.65
Mutation Taster		=100/0	polymorphism (auto)

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

dbSNP: rs805512; hg19: chr12-28118847;